WEBVTT 00:00:00.017 --> 00:00:07.517 Oh, this is a warning. We're in trouble, Tony. This is the Convergent Science Network podcast. 00:00:09.577 --> 00:00:13.277 Leading researchers in the domain of neuroscience, brain theory, 00:00:13.437 --> 00:00:19.377 and technology are interviewed by Paul Verschure and Tony Prescott. You ready? All right. 00:00:20.317 --> 00:00:24.797 Paul Verschure with the Convergent Science Network podcast together with Tony 00:00:24.797 --> 00:00:29.757 Prescott. And we're talking now with Mark Bloomberg, who was a speaker at our 00:00:29.757 --> 00:00:31.957 BCBT 2015 summer school. 00:00:32.497 --> 00:00:37.777 And Mark, you were linking in your talk and also in the research that you've 00:00:37.777 --> 00:00:42.737 got some time, sleep and the development of the motor system. 00:00:44.077 --> 00:00:49.617 So, and in some ways also telling us that sleep is doing a lot more than just sleeping. 00:00:50.257 --> 00:00:54.817 So what's really the link here between the development of the motor system and sleep? 00:00:56.017 --> 00:00:59.177 Well, what you see in early development, one of the things that marks sleep 00:00:59.177 --> 00:01:02.177 in early development is the fact that you, first of all, you're sleeping a lot more. 00:01:02.417 --> 00:01:07.857 And even more, when you're young, you're having a high proportion of REM sleep, 00:01:07.897 --> 00:01:09.577 what we also call active sleep. 00:01:09.697 --> 00:01:13.477 And what makes active sleep active sleep is the fact that you are engaging, 00:01:13.597 --> 00:01:19.817 you have an activated nervous system, you have a loss of the ability to have high muscle tone. 00:01:19.817 --> 00:01:22.817 But even though you have low muscle tone during active sleep, 00:01:23.097 --> 00:01:28.057 infants are producing a lot of motor activity in the form of these myoclonic 00:01:28.057 --> 00:01:29.857 twitches, just twitches for short. 00:01:30.037 --> 00:01:34.977 And so what happens during these twitches is that you are activating muscles, 00:01:35.197 --> 00:01:37.717 you're moving limbs, you're moving eyes, you're moving whiskers. 00:01:37.977 --> 00:01:41.137 And there are sensory consequences to those movements, which, 00:01:41.197 --> 00:01:45.797 as we've shown over the last 10 years or so, cascades through the nervous system. 00:01:46.562 --> 00:01:49.502 And so the question we've had is what, you know, although these twitches have 00:01:49.502 --> 00:01:54.482 largely been thought of as remnants of dreams, you know, the old wives tale 00:01:54.482 --> 00:01:57.642 of dogs chasing rabbits in their dreams, 00:01:58.102 --> 00:02:01.622 what we think is happening is in fact that these twitches are not epiphenomenal, 00:02:01.622 --> 00:02:05.682 are not byproducts, but are products of the nervous system that play a role 00:02:05.682 --> 00:02:11.282 in self-organizing or bootstrapping the sensory motor system to create the fundamental 00:02:11.282 --> 00:02:13.482 structure that makes wake movements possible. 00:02:13.942 --> 00:02:17.462 So now what are the basic properties of these twitches? 00:02:17.642 --> 00:02:20.542 The basic properties are first that they are discrete. 00:02:20.682 --> 00:02:24.382 That when you look at twitching in slow motion as we have you see that individual 00:02:24.382 --> 00:02:26.222 joints are activated at the same time. 00:02:26.382 --> 00:02:30.702 Some animals the flurry of activity can be so great it's been they've been confused 00:02:30.702 --> 00:02:35.502 with seizure activity or people think that all these movements are happening simultaneously. 00:02:36.062 --> 00:02:42.002 But in fact they are highly highly discrete. We rarely see simultaneous twitches 00:02:42.002 --> 00:02:43.942 in multiple joints. It's a rarity. 00:02:44.182 --> 00:02:48.202 Another feature is that they are occurring against this background of high muscle 00:02:48.202 --> 00:02:50.462 tone and of low muscle tone, rather. 00:02:50.722 --> 00:02:53.942 And so that becomes important when you're thinking about producing a movement 00:02:53.942 --> 00:02:56.602 and getting feedback in return of that movement. 00:02:56.722 --> 00:03:00.882 You want it to happen in a situation where there's a high signal-to-noise ratio, 00:03:01.222 --> 00:03:04.082 where the signal you're getting back is clear. 00:03:04.909 --> 00:03:10.929 Um, the metaphor I like to use is a submarine where people are doing echolocation or sonograms. 00:03:11.349 --> 00:03:14.509 Um, um, sonogram? No. What is it called? 00:03:15.009 --> 00:03:18.109 Um, you know. Sonar. sonar thank you thank you word choice 00:03:18.109 --> 00:03:21.069 problem here um when you do sonar you know like every movie 00:03:21.069 --> 00:03:24.009 that's ever been done with a submarine the captain tells everybody 00:03:24.009 --> 00:03:27.209 to be quiet and then they send out you know a single ping and they 00:03:27.209 --> 00:03:30.009 get a they get a feedback from that i think that's 00:03:30.009 --> 00:03:32.889 what's happening during twitching you're shutting down the system and 00:03:32.889 --> 00:03:35.709 then you're sending you're pinging your your limbs you're pinging your 00:03:35.709 --> 00:03:38.609 whiskers you're pinging your eyes and you're getting feedback in 00:03:38.609 --> 00:03:41.589 response to that that then allows you to make sense of uh 00:03:41.589 --> 00:03:44.629 of how your your your body is constructed and then 00:03:44.629 --> 00:03:47.629 finally the twitches themselves have spatio-temporal structure 00:03:47.629 --> 00:03:50.469 that is that they there are certain movements that are 00:03:50.469 --> 00:03:53.389 joint movements that are more likely to happen than other joint movements 00:03:53.389 --> 00:03:56.629 and we've chronicled some of those changes across development so 00:03:56.629 --> 00:03:59.629 all these things together tell us that twitching is not some you 00:03:59.629 --> 00:04:02.849 know mere random activation it's a highly structured 00:04:02.849 --> 00:04:05.529 a highly organized system so there's there's a 00:04:05.529 --> 00:04:08.649 trajectory of twitching um through development 00:04:08.649 --> 00:04:11.749 is there sort of in that it does it become more complex 00:04:11.749 --> 00:04:14.549 or is it just yes we've seen that the that the movements become 00:04:14.549 --> 00:04:17.229 you you end up with more multi-joint movements you end up 00:04:17.229 --> 00:04:21.289 with more complex movements over the six day differences that we've looked at 00:04:21.289 --> 00:04:25.489 from two days of age in a rat to eight days of age there is a documentable change 00:04:25.489 --> 00:04:31.529 in the structure of the twitching but now can we so what was the lowest level 00:04:31.529 --> 00:04:34.569 of at which the twitch can be expressed breast. 00:04:34.789 --> 00:04:37.729 That's a single muscle fiber. It's a group of muscle fibers. 00:04:37.809 --> 00:04:40.369 It's a, it's a synergy between multiple muscles. 00:04:40.489 --> 00:04:43.589 Yeah. Great question. What's the lowest level? Um, we don't know. 00:04:43.909 --> 00:04:47.549 So to move a limb, it probably takes at least many muscle fibers. 00:04:47.949 --> 00:04:50.429 We've, we don't think it's probably, we do not think. 00:04:51.460 --> 00:04:53.040 We suspect it's not at the level 00:04:53.040 --> 00:04:55.700 of single muscle fibers. It's probably at the level of muscle groups. 00:04:56.940 --> 00:05:00.980 But just due to the problem of measuring individual muscle fibers, 00:05:01.060 --> 00:05:03.140 we haven't been able to technically work that one out. 00:05:03.920 --> 00:05:08.000 Okay, but then how far up would that go? 00:05:08.180 --> 00:05:12.100 Would it go to the level of the movement of a whole limb? 00:05:12.320 --> 00:05:14.660 Like I move my arm and my hand and my fingers? 00:05:14.940 --> 00:05:18.080 Or is there an upper bound to what you would call a twitch? 00:05:18.680 --> 00:05:24.000 Well, a twitch is a movement of any given, in any given direction for any given joint. 00:05:24.380 --> 00:05:28.140 But you can have a bout of twitching in which you can have multiple joints, 00:05:28.300 --> 00:05:31.400 even across multiple limbs, that occur in a very rapid sequence. 00:05:31.660 --> 00:05:36.960 And we've used about 50 milliseconds as our cutoff for defining one twitch to 00:05:36.960 --> 00:05:39.120 another twitch to another twitch as defining a bout. 00:05:39.560 --> 00:05:42.820 And when you look at that very fine time scale, I mean 50 milliseconds is pretty 00:05:42.820 --> 00:05:46.600 short, what you see is there's certain sorts of movements that are very likely. 00:05:46.780 --> 00:05:49.840 So one thing that you you might have is that your shoulder might bring your 00:05:49.840 --> 00:05:53.520 fist towards your body of your right limb, and very quickly after that, 00:05:53.580 --> 00:05:56.480 you may have the same sort of movement in your left limb. 00:05:56.740 --> 00:05:59.440 And those sorts of movements, what we call homologous movements, 00:05:59.580 --> 00:06:02.440 a movement towards the body of your right, movement towards the body of your 00:06:02.440 --> 00:06:04.460 left, that happen with a great frequency. 00:06:04.660 --> 00:06:08.460 And that can be attributed to certain aspects of the spinal circuitry connecting 00:06:08.460 --> 00:06:09.960 the right to the left limb. 00:06:10.180 --> 00:06:15.080 So we've been trying to dissect out those sorts of highly probable and low probable. 00:06:15.840 --> 00:06:20.080 Events in these more complex twitches. 00:06:20.520 --> 00:06:27.240 What do we know about the development of the motor pattern circuits that are 00:06:27.240 --> 00:06:28.300 underlying some of this? 00:06:28.360 --> 00:06:31.700 Are they developing during this period, or are they more or less in place? 00:06:32.080 --> 00:06:35.380 They're greatly developing. So initially, even across the early ages that I 00:06:35.380 --> 00:06:39.320 was talking about today, the spinal cord plays an enormous role initially in 00:06:39.320 --> 00:06:42.340 the production of a lot of these movements, especially in the fetal situation. 00:06:42.340 --> 00:06:49.420 By the time these animals are born, you're already getting brainstem contributions to that as well. 00:06:49.500 --> 00:06:53.100 So you're now adding a brainstem motor component to your spinal motor component. 00:06:53.260 --> 00:06:56.040 For the purposes of twitching, that's all you have. 00:06:56.360 --> 00:07:00.320 But even for the purposes of wake movement, at those ages, the cortex is not 00:07:00.320 --> 00:07:04.220 playing any role at all, as far as we can tell, in the production of movement. 00:07:04.220 --> 00:07:08.160 The cortex is mostly receiving information and laying down those early structures. 00:07:08.400 --> 00:07:11.200 They do not have a lot of motor outflow. So for the most part, 00:07:11.300 --> 00:07:15.820 this period of infancy in rats, which is roughly the last trimester in humans, 00:07:15.980 --> 00:07:19.780 this is largely a period of brainstem control of movement. 00:07:20.718 --> 00:07:24.258 Very little cerebellar control directly cerebellum doesn't really do a lot of 00:07:24.258 --> 00:07:28.478 direct motor control um so the the brain stem is doing most of the heavy lifting 00:07:28.478 --> 00:07:33.398 are we talking about the first 10 days of rat roughly maybe the first week or 00:07:33.398 --> 00:07:36.158 so yeah so they're mostly in in the the nest, 00:07:36.698 --> 00:07:40.198 not moving around very much presumably they do move i mean they the movements 00:07:40.198 --> 00:07:43.878 that they have during wake their eyes are closed uh the visual system is limited 00:07:43.878 --> 00:07:46.898 they're getting some light but not a lot because their eyes are sealed until 00:07:46.898 --> 00:07:50.318 they're 15 days of age their their interactions are mostly huddling, 00:07:50.398 --> 00:07:52.378 so they're interacting with their litter mates, 00:07:52.558 --> 00:07:54.498 they're diving into the huddle, they're coming out of the huddle, 00:07:54.578 --> 00:07:59.378 and then they are seeking the mothers for milk and protection. 00:08:00.198 --> 00:08:05.078 And if you put them outside the nest, they can engage in some locomotor activity. 00:08:05.378 --> 00:08:08.778 But it's fairly limited at those ages. They're dragging themselves along, 00:08:08.958 --> 00:08:10.018 aren't they? Yeah, exactly. 00:08:10.178 --> 00:08:12.858 And it's not until they're about, you know, weaning is a rough, 00:08:12.958 --> 00:08:14.318 you know, when they actually get independent. 00:08:14.498 --> 00:08:18.858 But around 21 days of age, they're very ambulatory and they're moving as you 00:08:18.858 --> 00:08:20.338 would expect of an adult, pretty much. 00:08:20.538 --> 00:08:26.358 But to qualify as a twitch, we are talking about, let's say, 00:08:26.378 --> 00:08:28.538 a time window of about 50 milliseconds duration. 00:08:29.498 --> 00:08:35.778 But also, I would assume there's a lack of coordination because otherwise I 00:08:35.778 --> 00:08:38.758 can make a goal-oriented movement and say, oh, this is a sequence of twitches. 00:08:39.278 --> 00:08:46.218 So there must be a minimal level of, let's say, coordination across multiple twitches. 00:08:46.218 --> 00:08:50.238 So where where do we draw the boundary there in terms of the coordination across 00:08:50.238 --> 00:08:53.338 twitches okay well what defines a twitch that when i said 50 milliseconds i 00:08:53.338 --> 00:08:57.078 meant the difference between two twitches two independent ones the twitches 00:08:57.078 --> 00:08:59.098 themselves are very fast on the order of five, 00:08:59.818 --> 00:09:02.798 milliseconds but it's hard to know when you start when you stop those sorts 00:09:02.798 --> 00:09:08.698 of things some of the movement is active and some of it is passive in return um the the. 00:09:09.645 --> 00:09:13.145 So it's easy to distinguish a wake movement from a sleep movement. 00:09:13.325 --> 00:09:15.125 I think I showed you some examples today. 00:09:16.045 --> 00:09:21.405 When you see a baby or a rat when they're waking, what you see are very high amplitude movements. 00:09:21.545 --> 00:09:25.065 The movements of the limbs are typically, they have some relationship to one 00:09:25.065 --> 00:09:26.805 another. It can be an alternating movement. 00:09:27.325 --> 00:09:30.285 It can be a retraction of both limbs. It could be a yawn. 00:09:30.865 --> 00:09:35.205 It could be kicking. and those sorts of movements are happening when the muscle 00:09:35.205 --> 00:09:38.325 tone is high and the nervous system is in a different state. 00:09:38.565 --> 00:09:42.405 What distinguishes a twitch has to be the nature of the movement itself, 00:09:42.705 --> 00:09:48.005 how quick it occurs, and also the background activity, the low muscle tone, 00:09:48.185 --> 00:09:49.325 that general sense of relaxation. 00:09:49.945 --> 00:09:54.885 Anybody who has a dog or a cat or a baby or a person and you're watching them sleep, 00:09:55.005 --> 00:09:56.325 what you'll notice is, or if you've 00:09:56.325 --> 00:09:58.785 ever been on a bus and you've tried to sleep in an upright position, 00:09:58.785 --> 00:10:01.605 you feel terrible when you wake up and your neck 00:10:01.605 --> 00:10:04.705 has your head has fallen over and you're because 00:10:04.705 --> 00:10:07.545 your neck is completely relaxed and that is what happens in 00:10:07.545 --> 00:10:10.765 REM sleep it's that relaxation of the muscles that defines 00:10:10.765 --> 00:10:13.665 REM sleep in addition to this this sort of 00:10:13.665 --> 00:10:17.405 this phasic this fast activity that occurs with twitching all 00:10:17.405 --> 00:10:20.325 of those things under normal conditions have to occur for 00:10:20.325 --> 00:10:23.125 you to say that it's a twitch but for just to say 00:10:23.125 --> 00:10:26.025 it's REM sleep there also has to be some oscillatory property in the 00:10:26.025 --> 00:10:28.885 brain i mean it's not necessarily okay i mean 00:10:28.885 --> 00:10:32.545 there comes a point when you can measure eg activity and 00:10:32.545 --> 00:10:35.325 that eg activity as bears more of a resemblance to 00:10:35.325 --> 00:10:41.625 waking than it does to to uh um to slow wave sleep or quiet sleep um so waking 00:10:41.625 --> 00:10:45.245 and REM sleep have very similar eg patterns right but it's not rhythmic it's 00:10:45.245 --> 00:10:50.545 highly desynchronized um so there is you know there are rhythms that occur during 00:10:50.545 --> 00:10:53.965 during active sleep but they're not the ones we so there is a little, 00:10:54.425 --> 00:10:59.565 risk of circularity here if you define REM sleep in terms of exhibiting twitching. 00:11:00.247 --> 00:11:02.727 And then you want to say twitching happens during REM sleep? 00:11:02.927 --> 00:11:04.787 No, it's also with the muscle atonia. 00:11:04.967 --> 00:11:08.567 So the muscle atonia is the key for that. That's right. 00:11:08.787 --> 00:11:13.407 I mean, you need more than one component to define a state, and those are the two. 00:11:13.607 --> 00:11:17.627 But now we have plenty of other examples of brain activity patterns that we 00:11:17.627 --> 00:11:21.247 see during REM sleep that we don't see in other states. Even in these pups? Yes. 00:11:21.487 --> 00:11:25.607 And they also do the sort of passive sleep as well as the active sleep? 00:11:26.107 --> 00:11:29.707 What's called quiet sleep? Yeah. It's very brief in these animals, 00:11:29.827 --> 00:11:34.827 and it's very difficult to distinguish from quiet waking because they're so immature. 00:11:35.187 --> 00:11:40.287 And so there comes a point around 11 days after age when quiet sleep can be 00:11:40.287 --> 00:11:42.107 defined on the basis of EEG activity. 00:11:42.327 --> 00:11:46.547 But prior to that age, it's very hard to distinguish. A quiet animal is just 00:11:46.547 --> 00:11:49.447 a quiet animal, and their eyes don't open. 00:11:49.507 --> 00:11:53.727 So you don't have a lot of the components that we have in an adult. 00:11:54.347 --> 00:12:01.007 But in some sense if we follow your your sonar example now if we if we remove 00:12:01.007 --> 00:12:05.247 muscle tone and i see the twitches in some sense this is if you want the central 00:12:05.247 --> 00:12:09.347 nervous system talking to the skeletal muscle system and then you could say 00:12:09.347 --> 00:12:12.387 well the muscle twitch or the twitches i observe. 00:12:13.167 --> 00:12:18.267 Are if you want the lowest level of resolution the brain has available to really 00:12:18.267 --> 00:12:25.267 talk to the skeletal muscle system and as such this would be let's say a movement primitive okay. 00:12:26.187 --> 00:12:28.947 Would you be happy with with that interpretation or you 00:12:28.947 --> 00:12:32.287 look at it differently is it more like a random driving of the skeletal muscle 00:12:32.287 --> 00:12:36.067 system in a way that is not related to actually the control of the skeletal 00:12:36.067 --> 00:12:39.887 muscle system well so now so so we've we had a little bit of discussion in the 00:12:39.887 --> 00:12:43.487 talk about you know primitives and what they mean and so let me just it's important 00:12:43.487 --> 00:12:47.327 for me to state where I come from philosophically on that issue. 00:12:47.507 --> 00:12:51.907 So I come from a school of thought that, you know, my training and my background 00:12:51.907 --> 00:12:57.867 is in an area that's, you know, it's a fundamental developmental perspective. 00:12:58.327 --> 00:13:02.527 And the framework that's adopted by people like me is called the developmental 00:13:02.527 --> 00:13:06.147 systems theory perspective framework, however you want to call it. 00:13:06.227 --> 00:13:09.927 And the point of it is, is really to sort of to get away from using certain 00:13:09.927 --> 00:13:16.527 types of words that we think can be traps to understanding the origins of any given system. 00:13:16.647 --> 00:13:20.387 And for people like me, I mean, I'm very interested in where things come from. 00:13:20.647 --> 00:13:24.027 And the problem with saying that something is a primitive is that it immediately 00:13:24.027 --> 00:13:28.687 evokes the notion that you get it for free, that you get it without developing it. 00:13:28.807 --> 00:13:32.487 But there is no aspect of the nervous system, there is no aspect of a biological 00:13:32.487 --> 00:13:34.167 system that does not first develop. 00:13:34.527 --> 00:13:38.847 So when you say primitive, So I would have to throw it back at you and say, 00:13:38.927 --> 00:13:40.307 well, what do you mean by a primitive? 00:13:40.647 --> 00:13:45.827 Because even the fundamental wiring up of that system has to occur through a 00:13:45.827 --> 00:13:49.387 variety of genetic, epigenetic, and activity-dependent processes. 00:13:50.267 --> 00:13:54.327 So there are no primitives in the nervous system. But I gave you a definition, right? 00:13:54.387 --> 00:13:58.007 Because I told you it's the lowest level of resolution in which the central 00:13:58.007 --> 00:14:00.047 nervous system can talk to the skeletal muscle system. 00:14:02.984 --> 00:14:05.664 If you want to define that as a primitive, then we've now defined primitive 00:14:05.664 --> 00:14:07.244 in a way that it's typically not defined. 00:14:07.484 --> 00:14:10.904 The way it's typically defined is to say that the wake movements, 00:14:11.144 --> 00:14:13.464 the goal-directed movements, certain things that animals do, 00:14:13.584 --> 00:14:16.864 alternating leg movements, for example, central pattern generators, 00:14:17.124 --> 00:14:18.224 that these are primitives. 00:14:18.544 --> 00:14:22.844 But as people are now showing more and more, even central pattern generators develop. 00:14:23.544 --> 00:14:27.444 So the thing that used to be called a primitive has now become a developmental product. 00:14:27.824 --> 00:14:30.604 And I think that that's, I think it's healthier to stay away from those sorts 00:14:30.604 --> 00:14:32.484 of things. but, you know, to the extent that you want. 00:14:32.984 --> 00:14:36.244 What's that? We need a word. We have to say, this is the lowest level of resolution 00:14:36.244 --> 00:14:37.824 that cannot be further divided. 00:14:38.124 --> 00:14:41.864 It's like an atom, right? But I think I agree with Mark here that it's relative. 00:14:42.064 --> 00:14:45.844 So you could say that from the point of view of the cortex, you might have a 00:14:45.844 --> 00:14:48.524 most primitive instantiated in the brainstem. 00:14:48.664 --> 00:14:52.684 But from the point of view of the brainstem, you have to assemble that out of 00:14:52.684 --> 00:14:55.724 components, which may be at the level of muscles. 00:14:56.144 --> 00:14:59.424 And then at the muscle level, you could break it down further. 00:14:59.424 --> 00:15:02.344 So yeah so i think you can use primitive but 00:15:02.344 --> 00:15:05.244 you have to say what you mean primitive with respect to what a little 00:15:05.244 --> 00:15:07.944 bit that's what i was saying where this is the lowest level at which the 00:15:07.944 --> 00:15:10.844 central nervous system can drive the skeletal muscle 00:15:10.844 --> 00:15:15.004 system i'm not sure that's true so let's let's let's explore that for a second 00:15:15.004 --> 00:15:18.584 so we're very very early in development in rats in the fetal period that would 00:15:18.584 --> 00:15:22.824 be true for the maybe that's true for humans as well but earlier in the fetal 00:15:22.824 --> 00:15:28.224 period um muscles can skin it's called myogenic activity you can have muscle activity 00:15:28.364 --> 00:15:33.104 that occurs without any neurogenic, any neural, any brain, any central nervous system input. 00:15:33.384 --> 00:15:36.404 And as you, as you get, as you move, move through development, 00:15:36.604 --> 00:15:39.484 the spinal cord is doing a lot of this activity on its own. 00:15:39.544 --> 00:15:42.024 And then eventually, as I said earlier, then the brainstem starts to do more. 00:15:42.284 --> 00:15:46.064 So the mode, there could be a motor primitive very early in fetal development 00:15:46.064 --> 00:15:47.364 that's just at the level of muscle. 00:15:47.464 --> 00:15:49.864 Then you can have another motor primitive that's at the level of spinal cord, 00:15:49.924 --> 00:15:50.724 another one of the brainstem. 00:15:50.964 --> 00:15:53.984 And then at that point, I think the concept of a primitive loses its force. 00:15:54.404 --> 00:15:57.044 You know, at that point, I would rather just say what we are 00:15:57.044 --> 00:15:59.684 describing rather than using a word that has such a 00:15:59.684 --> 00:16:02.504 history you know so that's that's my problem and i think 00:16:02.504 --> 00:16:05.384 we do need a word and then we have to invent it right here 00:16:05.384 --> 00:16:11.504 right now because no that's not good enough i think because what we have to 00:16:11.504 --> 00:16:17.644 deal with is the question are we driving these muscle groups or muscle fiber 00:16:17.644 --> 00:16:22.044 groups in some random way as our sonar example would be look Look, 00:16:22.064 --> 00:16:23.524 I'm exploring my environment. 00:16:23.564 --> 00:16:25.684 I'm exploring my muscle, muscular system. 00:16:25.904 --> 00:16:28.564 I'm picking it. I get stuff back randomly. 00:16:29.640 --> 00:16:34.380 Or am I driving it in a way that already anticipates controlling that same system? 00:16:34.520 --> 00:16:40.040 And now I have to drive it in a way that is specific to the control I will perform 00:16:40.040 --> 00:16:41.760 later during wakefulness. 00:16:42.060 --> 00:16:48.120 And then it must be a unit, a basic unit, that I can assemble into behaviors. 00:16:49.020 --> 00:16:53.920 Well, so I'm going to argue for a more iterative process in this whole thing, 00:16:54.020 --> 00:16:57.780 where you start off with these, and they can't even be random movements, 00:16:57.780 --> 00:17:01.520 and there's some evidence in fetuses that they start off when they're spinally 00:17:01.520 --> 00:17:03.080 generated, that they look random. 00:17:03.860 --> 00:17:07.080 And they change over time. And then the question becomes, why do they change? 00:17:07.200 --> 00:17:10.220 And when you start getting into the issue of any kind of a loop, 00:17:10.500 --> 00:17:15.780 you know, anytime you have an output and an input, you can't say what causes what at that point. 00:17:16.080 --> 00:17:19.860 So, you know, you have an activity pattern, you have a motor outflow, 00:17:20.000 --> 00:17:24.080 but then you get information about that motor outflow and that modifies the 00:17:24.080 --> 00:17:29.940 next iteration of that system. And so the system keeps getting more and more complex over time. 00:17:30.100 --> 00:17:35.180 So what initially starts random starts to look structured and eventually becomes goal-directed. 00:17:35.300 --> 00:17:38.740 And then the process of, well, what does that mean to be goal-directed? 00:17:38.820 --> 00:17:42.540 And now we're talking about how you produce models of the outside world inside 00:17:42.540 --> 00:17:46.020 of your head that allow you to control your limbs in very, very productive ways. 00:17:46.020 --> 00:17:50.480 And now we're getting into the issues of all the computational processes that are involved. 00:17:50.780 --> 00:17:56.020 We're only beginning to understand that system from the perspective anyway that I'm taking with this. 00:17:56.140 --> 00:18:02.020 And so I'm trying to avoid certain assumptions that come out of non-developmental 00:18:02.020 --> 00:18:05.980 work because I want to try to understand how the thing develops without being 00:18:05.980 --> 00:18:09.460 bound by concepts that are outside of that perspective. 00:18:09.460 --> 00:18:15.760 I guess that one of the differences may be that we are interested in assembling 00:18:15.760 --> 00:18:23.160 control systems for things like robots, and there the notion of primitive is very useful. 00:18:23.160 --> 00:18:29.580 So you can say, I have some device that I know can control the arm and move it to a certain place. 00:18:30.020 --> 00:18:34.120 Therefore, I can just, at a higher level, just command the position I want to 00:18:34.120 --> 00:18:39.900 move my arm to, rather than worry about how I coordinate the different joints to make that movement. 00:18:40.200 --> 00:18:45.260 And that definition of primitive is really useful then in robot control. 00:18:45.260 --> 00:18:51.380 And I guess it's an interesting question as to whether that's useful then to 00:18:51.380 --> 00:18:53.760 think about in terms of hierarchy of brain systems. 00:18:54.140 --> 00:19:00.120 For instance, people often think about the superior colliculus as being a device 00:19:00.120 --> 00:19:04.040 that can generate head and eye movements to a particular location in space, 00:19:04.300 --> 00:19:07.900 so that a system talking into the colliculus just has to give it a coordinate. 00:19:08.300 --> 00:19:13.560 Right. I think that's absolutely right. Right. So the point I think my challenge 00:19:13.560 --> 00:19:17.840 back to the robotics perspective is that. 00:19:18.513 --> 00:19:21.833 If you have the notion of a primitive, if that becomes a useful concept in robotics, 00:19:22.413 --> 00:19:27.573 but it turns out not to be a useful concept for actual biological systems, 00:19:27.833 --> 00:19:32.653 then might there be some value in thinking about how you get to a primitive 00:19:32.653 --> 00:19:36.453 and how you imagine the developmental process, and might that play a role in 00:19:36.453 --> 00:19:38.993 creating robots that are more flexible and adaptable? 00:19:40.053 --> 00:19:43.353 So I can understand that the concept of primitive is useful, 00:19:43.493 --> 00:19:49.333 perhaps, and safe from my perspective. As long as you say that it's a primitive as of time T. 00:19:49.613 --> 00:19:51.713 As of this moment, it's a primitive for that. 00:19:52.013 --> 00:19:56.353 But then it doesn't tell you how you got there. To agree on the fact that these 00:19:56.353 --> 00:19:59.473 primitives are acquired is not a problem. 00:19:59.973 --> 00:20:04.913 But it is a stable representational structure that helps you to perform a certain operation. 00:20:05.533 --> 00:20:08.553 And it's also a commitment to saying brains are controllers in the end. 00:20:08.613 --> 00:20:09.533 They control the skeletal muscle 00:20:09.533 --> 00:20:12.493 system. Well, I guess I agree with you on that point. I mean, I'm fine. 00:20:12.613 --> 00:20:15.353 I wish that all people use the word primitive the way you're using it. 00:20:15.353 --> 00:20:20.253 Unfortunately we found each other mark unfortunately unfortunately 00:20:20.253 --> 00:20:23.553 people have used the word primitive to do a lot of mischief sure and 00:20:23.553 --> 00:20:26.473 and it's the mischief i'm trying to avoid by by being 00:20:26.473 --> 00:20:30.513 cagey about the word okay but but at least we resolve this obstacle now i think 00:20:30.513 --> 00:20:35.273 we have we're ready to move on exactly so this is very good but now through 00:20:35.273 --> 00:20:40.533 development do you see that twitches the twitching behavior becomes more stereotyped 00:20:40.533 --> 00:20:45.513 in an acquired fashion i emphasize So it loses variability over development? 00:20:45.893 --> 00:20:51.753 We don't know. We did do an entropy measure for the multi-joint activity. 00:20:51.873 --> 00:20:56.353 And we did find interesting relationships between how entropy and the frequency 00:20:56.353 --> 00:20:57.873 of movements changed over development. 00:20:58.193 --> 00:21:07.353 So it appeared as if the multiple joint movements that were composed of multiple twitches, 00:21:07.893 --> 00:21:10.873 though the entropy that is the organization of that system 00:21:10.873 --> 00:21:14.233 um it became more ordered over time over 00:21:14.233 --> 00:21:18.113 a very short period of time so that it appeared and and the ones that were more 00:21:18.113 --> 00:21:22.713 ordered became more frequent over time so there seems to be an interesting almost 00:21:22.713 --> 00:21:27.473 like a selectionist like a darwinian process and choosing which types of movements 00:21:27.473 --> 00:21:32.993 are going to persist to the next day or the next week of the animal's life well we don't yet know. 00:21:33.980 --> 00:21:38.100 Is when you start getting into systems that are much more highly developed, 00:21:38.220 --> 00:21:42.660 much more complex, capable of really complex goal-directed reaching movements, 00:21:42.920 --> 00:21:45.560 locomotion, you know, much more complex things. 00:21:45.660 --> 00:21:49.040 We don't have a good sense yet of how well twitching looks in those situations. 00:21:49.280 --> 00:21:55.300 I have a colleague sent me a video of a racehorse who appeared to be in REM sleep. 00:21:55.480 --> 00:21:59.940 I mean, the horse was on its side and it was moving its legs, 00:22:00.040 --> 00:22:03.220 you know, in this beautiful synchronous racehorse-y kind of a way. 00:22:03.220 --> 00:22:04.840 And racehorses rely more heavily 00:22:04.840 --> 00:22:07.640 on their hind limbs than they do on their forelimbs for propulsion. 00:22:07.960 --> 00:22:11.780 And so then the question is, well, you know, somebody might say that the racehorse 00:22:11.780 --> 00:22:15.680 was dreaming about its race, and I would say that it was engaging in spontaneous 00:22:15.680 --> 00:22:21.400 activity during REM sleep that is sort of a way of training up its or practicing its system. 00:22:21.560 --> 00:22:23.880 But we don't, that has not been documented. 00:22:24.180 --> 00:22:26.520 But those two things could be the same. They could be, yeah. 00:22:26.600 --> 00:22:30.340 Yeah. So there was some cortical activity that went alongside of that. 00:22:30.340 --> 00:22:33.580 But here we get into this really interesting debate that I'm having with some 00:22:33.580 --> 00:22:37.880 colleagues about whether or not the motor cortex plays any role at any age in 00:22:37.880 --> 00:22:41.340 the production of twitching. And I would argue there is no evidence that the 00:22:41.340 --> 00:22:43.720 cortex plays a role in twitching. But it might not even be motor cortex. 00:22:43.780 --> 00:22:47.860 It might be visual cortex, the animals visualizing, you know, the track. 00:22:48.280 --> 00:22:52.540 Yeah, but how do you go from the visual cortex to motor control without engaging the motor cortex? 00:22:52.880 --> 00:22:56.640 Oh, well, you go via the brainstem, sort of via the basal ganglia. 00:22:56.640 --> 00:23:00.940 Yeah, no, there is no evidence that any part of the forebrain is playing a role 00:23:00.940 --> 00:23:03.000 yet, but it remains to be proven. 00:23:03.260 --> 00:23:10.200 But my argument to my clinical and other sleep research friends is to say that we need evidence. 00:23:10.380 --> 00:23:14.120 There is no evidence right now. And there are recordings from the visual cortex, 00:23:14.300 --> 00:23:16.040 which also support that claim. 00:23:16.360 --> 00:23:20.060 Right. But now in development, do I lose muscle fiber that I'm not twitching enough? 00:23:20.440 --> 00:23:23.680 We don't know. I mean, we do know that twitching is happening close to the age 00:23:23.680 --> 00:23:29.920 that you start to lose polyinnervation of muscles, but there's never been a 00:23:29.920 --> 00:23:30.820 direct link between those. 00:23:31.000 --> 00:23:33.420 Okay, but that's a potential functional role as well, right? 00:23:33.640 --> 00:23:37.600 It is, I mean, and there's another one as well, which has been established for 00:23:37.600 --> 00:23:42.000 movement, which is that if you don't move your limbs as a fetus, your joints will fuse. 00:23:42.240 --> 00:23:46.300 Right. And so it's important for maintaining healthy bones and healthy joints 00:23:46.300 --> 00:23:48.360 when you're very early in development. 00:23:48.360 --> 00:23:51.000 And you need to move them or they fuse and then you're out of 00:23:51.000 --> 00:23:56.260 luck yeah but now you you you contrasted your your view on on on the role of 00:23:56.260 --> 00:24:01.980 twitching in in sleep with the idea of reference copy yes right or corral discharge 00:24:01.980 --> 00:24:07.760 and you you don't at least in in the way you presented it you you seem to see 00:24:07.760 --> 00:24:09.440 a difference between the two. 00:24:10.367 --> 00:24:13.827 So what would be that difference between twitching patterns, 00:24:14.087 --> 00:24:17.807 the role of twitching in the developing nervous system, and the role of an afferent copy? 00:24:18.667 --> 00:24:23.747 Well, so the results we have so far suggest that what distinguishes movements 00:24:23.747 --> 00:24:28.007 that we make when we're awake, this is just the data are only for young animals. 00:24:28.087 --> 00:24:33.007 So it's important to be clear about that. But the movements that an infant makes 00:24:33.007 --> 00:24:36.747 when it is awake actually involves, 00:24:37.047 --> 00:24:42.307 when you're moving your limb in the air or whatever, the sensory information 00:24:42.307 --> 00:24:47.407 that could be coming back from that limb, the proprioceptors and so on, 00:24:47.527 --> 00:24:50.707 the information from that is being shut down, 00:24:50.867 --> 00:24:54.027 prevented from making its way into the brain. 00:24:54.027 --> 00:24:58.487 Whereas when you twitch during your sleep, that information flows freely through. 00:24:58.867 --> 00:25:04.767 And we take that as evidence that that's why twitching is distinct and why it could be important. 00:25:05.387 --> 00:25:10.947 Now, in order to gate that information when you're awake, we posited that this 00:25:10.947 --> 00:25:15.647 corollary discharge process is engaged, and we now have direct evidence that that is the case. 00:25:15.707 --> 00:25:19.467 If we inhibit that corollary discharge phenomenon from occurring, 00:25:19.687 --> 00:25:24.947 we now allow information from during wakefulness to move into the brain from the wake movements. 00:25:24.947 --> 00:25:30.987 So that's one aspect of how the corollary discharge system can modulate sensory 00:25:30.987 --> 00:25:34.647 inflow into the brain during sleep versus wake. 00:25:35.907 --> 00:25:38.687 But that's just one feature of all this. 00:25:39.287 --> 00:25:43.287 I think of this as, you know, this is very much what you would expect on what 00:25:43.287 --> 00:25:48.067 people do with what people have found in adults, where the amount of reafference, 00:25:48.127 --> 00:25:52.427 the amount of information coming from waking limbs is very, very low when we're awake. 00:25:52.427 --> 00:25:54.867 And I was at first a little bit surprised by this. 00:25:54.907 --> 00:26:00.227 You know, I'm sitting there, people listening to the podcast can't tell this, 00:26:00.327 --> 00:26:04.187 but if I'm moving my arms in the air, and anybody can move their arms in the 00:26:04.187 --> 00:26:06.987 air, they can even close their eyes while they move their arms in the air. 00:26:08.027 --> 00:26:11.227 They have a very strong sense that they are moving their arms and they have 00:26:11.227 --> 00:26:13.967 a sense that that's sensory, that something sensory is happening. 00:26:14.527 --> 00:26:20.307 But motor control people who I've talked to about this say that not only are you not, 00:26:20.407 --> 00:26:23.307 the reason why you have that, what they would call an illusion of that, 00:26:23.387 --> 00:26:27.567 is because you have a computational model in your brain which is telling you 00:26:27.567 --> 00:26:30.147 that this is what you should be doing. This is what you should be feeling. 00:26:31.684 --> 00:26:35.824 So it becomes an illusion of a sensation that you are moving your arms in the 00:26:35.824 --> 00:26:39.124 air as opposed to what's happening, we think, in twitching when you actually 00:26:39.124 --> 00:26:42.964 are getting feedback that is changing brain activity. 00:26:43.204 --> 00:26:46.384 So I think that's what was surprising 00:26:46.384 --> 00:26:50.704 to us is that we saw this system functioning as early as we found it. 00:26:50.704 --> 00:26:56.204 So in your opinion, then, the twitching feedback is really a signal that is 00:26:56.204 --> 00:26:59.204 closely driven by the muscles themselves, 00:26:59.404 --> 00:27:04.224 while the corollary discharge is more based on, let's say, a forward model that 00:27:04.224 --> 00:27:08.144 is making predictions about what you were supposed to do or what you are doing, etc. 00:27:08.624 --> 00:27:11.564 This is sort of the transition that you see there. Yeah, I mean, 00:27:11.584 --> 00:27:17.264 we think it's going to be, you know, we haven't identified the source of the 00:27:17.264 --> 00:27:21.264 signal that is shutting off, gating that activity during wakefulness, 00:27:21.444 --> 00:27:25.624 but we suspect it's going to be tightly related to exactly what you said about 00:27:25.624 --> 00:27:28.124 something related to a forward model. 00:27:29.184 --> 00:27:32.984 But we need to, you know, we suspect a few areas, but we haven't established 00:27:32.984 --> 00:27:40.164 yet. But it might mean that it also can be a cascade of incrementally more prediction-oriented 00:27:40.164 --> 00:27:43.944 feedback signals as opposed to just two different systems. 00:27:44.164 --> 00:27:47.464 Yes. So on what side are you there in the interpretation? 00:27:47.924 --> 00:27:50.504 Well, it's all one system with different states. So, you know, 00:27:50.524 --> 00:27:54.044 the whole system is simply being engaged differently when you're awake versus when you're asleep. 00:27:54.304 --> 00:27:58.484 So when you're awake, certain, I mean, we don't know the full range of parts 00:27:58.484 --> 00:27:59.564 of the brain that are active. 00:28:00.044 --> 00:28:02.924 We know a lot about sleep circuitry, but not nearly enough. 00:28:03.424 --> 00:28:05.904 But, you know, we're getting to a point now where we can say that, 00:28:05.924 --> 00:28:08.724 you know, with respect to certain aspects of the motor system, 00:28:08.904 --> 00:28:12.624 it is being engaged differently during wakefulness than it is during sleep. 00:28:12.844 --> 00:28:17.124 And understanding what we're trying, we're trying furiously to understand in 00:28:17.124 --> 00:28:21.624 the lab right now is what are the critical parts of that circuit that are responsible 00:28:21.624 --> 00:28:24.484 for these differences between the states. 00:28:24.484 --> 00:28:29.664 So the claim, just to be clear in my mind, is that when you generate an emotive 00:28:29.664 --> 00:28:31.564 command when you're awake, a copy of that command. 00:28:32.414 --> 00:28:35.334 Goes to a part of the brain which then 00:28:35.334 --> 00:28:38.494 uses that to compute the sensory experiences i 00:28:38.494 --> 00:28:41.814 might expect as a consequence of that movement right and 00:28:41.814 --> 00:28:47.314 then the ascending sensory signals are matched with that prediction and anything 00:28:47.314 --> 00:28:52.074 that i have been able to predict then gets you know cancelled out and doesn't 00:28:52.074 --> 00:28:59.714 go up to my brain that's now when i'm asleep and i twitch wherever that motor command is coming from, 00:28:59.714 --> 00:29:06.294 I'm not going to send a copy to this comparator system so that any sensory signal 00:29:06.294 --> 00:29:09.994 that's coming in is going to carry on right up to, say, cortex. 00:29:10.434 --> 00:29:16.014 So although I initiated the movement, I still get the feedback as if I hadn't, 00:29:16.034 --> 00:29:18.014 you know, as if it moved separately. 00:29:18.254 --> 00:29:22.714 That's right. That's the claim. Yeah. And I think the further claim that you're 00:29:22.714 --> 00:29:30.674 making is that that's useful because it helps then parts of the brain to self-organize, perhaps, 00:29:30.974 --> 00:29:34.774 because the sort of activity-dependent aspects of development, 00:29:35.034 --> 00:29:40.494 you need to know that you have muscles out there that are working and operating 00:29:40.494 --> 00:29:42.474 and that have feedback signals. 00:29:42.754 --> 00:29:49.274 That's a wonderful synopsis of exactly what I'm saying. And I want to try to 00:29:49.274 --> 00:29:50.694 drive this home to a listener. 00:29:51.014 --> 00:29:54.714 Remember, I started with certain types of anomalous individuals, 00:29:54.854 --> 00:29:58.114 whether it was that at Johnny Eck, who was missing his two hind legs. 00:29:58.926 --> 00:30:02.406 The dogs who are missing their two forelimbs or hind legs, that sort of adaptability 00:30:02.406 --> 00:30:04.586 is not something that you can program in. 00:30:04.826 --> 00:30:07.766 You can't say to the brain, you know, before you know that you're going to have, 00:30:07.766 --> 00:30:10.966 you're not going to have two limbs and now you're going to remap the brain. 00:30:11.366 --> 00:30:16.846 The point I try to make is that whether you're born atypically as a dog with 00:30:16.846 --> 00:30:21.546 just two forelegs or two hind legs, or you're, you're a typically born dog with 00:30:21.546 --> 00:30:23.606 four, um, with four legs, 00:30:23.726 --> 00:30:27.606 you need to map the body you have, not the body you're supposed to have. 00:30:27.826 --> 00:30:32.146 And really what happens in development is no matter whether you have a typical 00:30:32.146 --> 00:30:36.226 body or an atypical body, the same exact developmental processes are going to 00:30:36.226 --> 00:30:42.146 be involved in making sense of your body and in mapping your body and making it a functional system. 00:30:42.286 --> 00:30:45.146 You know, we've lost sight of the, you know, in the 19th century, 00:30:45.166 --> 00:30:48.206 one of the biggest things were these, you know, freak shows and side shows, 00:30:48.286 --> 00:30:51.326 as they were called at the time, the Bartholomew Fair in England, 00:30:51.526 --> 00:30:56.386 where all these different anomalous people and animals would be displayed. 00:30:56.586 --> 00:30:59.966 And people could see for their own eyes how amazing people could be, 00:31:00.046 --> 00:31:04.166 the so-called armless wonders, people who could use their feet to sew and to 00:31:04.166 --> 00:31:07.946 play the piano and to play the violin and shuffle a deck of cards, 00:31:08.106 --> 00:31:10.906 things that most people imagine you could never do with your feet. 00:31:10.986 --> 00:31:15.726 And yet, if you're born without arms, you learn how to use your feet in very unique ways. 00:31:15.866 --> 00:31:18.526 And I think this aspect of plasticity in a 00:31:18.526 --> 00:31:21.446 developing system is something that we that i just you 00:31:21.446 --> 00:31:24.166 know like to emphasize in this context but now in this 00:31:24.166 --> 00:31:27.046 so now we have to the concept sort of clear 00:31:27.046 --> 00:31:30.086 and also how these different control systems would then work together with 00:31:30.086 --> 00:31:36.546 respect to feedback from twitches and from an inference copy um now we can start 00:31:36.546 --> 00:31:39.826 to look also more at the structures that underlie this right and and one of 00:31:39.826 --> 00:31:43.346 the first structures you pointed out there was the red nucleus which is a brainstem 00:31:43.346 --> 00:31:49.386 motor nucleus and you see then the red nucleus as both the trigger of Twitch's. 00:31:50.203 --> 00:31:54.863 And the recipient of this first level of feedback from the twitch, 00:31:54.943 --> 00:31:57.543 is this really the first station in this whole cascade? 00:31:57.883 --> 00:32:01.543 The first station is probably a sensory motor loop within the spinal cord itself. 00:32:01.783 --> 00:32:05.443 But the first one within the brain is going to be the red nucleus and all of 00:32:05.443 --> 00:32:06.443 its associated structures. 00:32:06.943 --> 00:32:10.863 So the red nucleus is one of the most important, most studied of these structures. 00:32:11.143 --> 00:32:13.963 But what's really interesting is that, you know, people have looked comparatively 00:32:13.963 --> 00:32:17.943 at different animals with weird morphologies, you know, like an elephant. 00:32:17.943 --> 00:32:23.463 And what happens is that the trunk is actually controlled by a nucleus that's near the red nucleus. 00:32:23.743 --> 00:32:28.063 So different animals with different structures have different emphases on different 00:32:28.063 --> 00:32:30.683 parts of those brain areas. 00:32:30.883 --> 00:32:34.143 But the red nucleus is certainly part of it. It's important for twitching. 00:32:34.143 --> 00:32:37.603 If we lesion that area, twitching goes down precipitously. 00:32:37.923 --> 00:32:41.403 And it's also involved, of course, in waking motor activity. 00:32:41.403 --> 00:32:46.523 So, this is a nucleus that's going to do one sort of firing pattern when the 00:32:46.523 --> 00:32:49.203 animal's awake, and it's going to do a very different kind of firing pattern 00:32:49.203 --> 00:32:50.103 when the animal's asleep. 00:32:50.803 --> 00:32:56.423 So, the same basic system is being manipulated for different purposes at different times of the day. 00:32:56.603 --> 00:33:00.263 But on the brainstem, we also have other motor nuclei, like you might find motor 00:33:00.263 --> 00:33:03.443 in some particular formation, or the peduncle pontine nucleus. 00:33:04.083 --> 00:33:10.903 So, do you see the red nucleus as then a specialized nucleus for twitch, let's say, control? 00:33:11.583 --> 00:33:14.283 Or is it just one among several at that 00:33:14.283 --> 00:33:17.083 level of brain organization so if you lesion the red nucleus 00:33:17.083 --> 00:33:19.803 not only do you not not only do you 00:33:19.803 --> 00:33:23.003 not wipe out all twitching but your effect 00:33:23.003 --> 00:33:25.603 is only temporary so that there are other parts of the 00:33:25.603 --> 00:33:28.363 brain stem that can make up for it there are multiple sites in the 00:33:28.363 --> 00:33:31.203 brain that are responsible for producing twitching because the 00:33:31.203 --> 00:33:34.483 red nucleus is you know plays a bigger role with the forelimbs than it does 00:33:34.483 --> 00:33:37.303 with the hind limbs and there are going to be other areas they're going to play 00:33:37.303 --> 00:33:40.223 a role for different types of movements and so So what we're really talking 00:33:40.223 --> 00:33:44.883 about is a network of premotor nuclei that are interacting to produce and interacting 00:33:44.883 --> 00:33:48.443 with the cerebellum as well to produce the full range of movements that we're capable of. 00:33:49.723 --> 00:33:53.243 So then what's the next level? So now we close the loop over the red nucleus. 00:33:53.703 --> 00:33:55.823 And indeed, now you mentioned cerebellum. 00:33:56.383 --> 00:34:00.503 Do you see now the cerebellum again talking to the red nucleus to trigger twitches 00:34:00.503 --> 00:34:02.103 at the different spatial temporal scale? 00:34:02.803 --> 00:34:07.963 Or is structure now processing the feedback signals that come from the twitches 00:34:07.963 --> 00:34:09.183 generated by the red nucleus? 00:34:09.563 --> 00:34:13.323 So we think that the twitches are going to play a role in shaping the cerebellum, 00:34:13.343 --> 00:34:16.383 but we haven't seen any evidence yet that the cerebellum is affecting twitching. 00:34:17.163 --> 00:34:23.303 And we've done this by lesioning the output nucleus of the cerebellum. 00:34:23.343 --> 00:34:26.323 But that work is still ongoing. going. So we haven't published that yet. 00:34:26.363 --> 00:34:27.223 That's still happening. 00:34:27.463 --> 00:34:30.223 So the cerebellum, though, is certainly part of this whole process. 00:34:30.303 --> 00:34:34.583 How it actually shapes twitching, we have not yet established that. But you did show that. 00:34:35.304 --> 00:34:41.424 The twitch correlates very strongly with a complex spike-like response in the 00:34:41.424 --> 00:34:45.064 cerebellum, at least the multi-unit level in the cerebellar cortex. 00:34:45.184 --> 00:34:49.544 So is that the link that you... Yes. Well, the cerebellum, the Purkinje cells 00:34:49.544 --> 00:34:52.704 in the cerebellum are definitely paying attention to twitches. 00:34:53.044 --> 00:34:56.184 Twitches are a very strong driver of cerebellar activity. 00:34:56.404 --> 00:35:00.464 And we're also recording from the deep cerebellar nuclei, which are the output nuclei, 00:35:00.584 --> 00:35:03.944 and they also are strongly um i'm receiving um 00:35:03.944 --> 00:35:06.904 information about twitches so the whole system is very 00:35:06.904 --> 00:35:09.844 much attuned to what's happening with these uh twitches during 00:35:09.844 --> 00:35:12.744 REM sleep but then you move up to other that's that's 00:35:12.744 --> 00:35:15.384 another sensory motor loop that gets closed with it 00:35:15.384 --> 00:35:18.084 that runs over the inferior olive essentially and it goes back to the 00:35:18.084 --> 00:35:22.064 red nucleus so the output the deep cerebellar nuclei project back to the red 00:35:22.064 --> 00:35:26.904 nucleus and presumably is modulating its output and all of these systems have 00:35:26.904 --> 00:35:34.264 to be you know to mapped in a topographically organized way so that a signal 00:35:34.264 --> 00:35:36.684 coming out of the red nucleus is going to activate the forelimb, 00:35:36.684 --> 00:35:39.764 and then the forelimb is going to feed back and affect certain parts of the cerebellum, 00:35:39.804 --> 00:35:42.324 which is going to go back and affect a certain part of the red nucleus that 00:35:42.324 --> 00:35:43.964 produced the signal in the first place. 00:35:44.124 --> 00:35:47.184 If you don't have that kind of convergence of output and input, 00:35:47.384 --> 00:35:49.204 you're going to have a disorganized motor system. 00:35:49.504 --> 00:35:53.764 But is that the example of the comparator also that Tony talked about earlier in your mind? 00:35:54.464 --> 00:35:57.864 The comparator is really more about what happens when you're awake. 00:35:58.824 --> 00:36:01.104 Yeah, but still you have to train it up. You do have to train it up. 00:36:01.104 --> 00:36:03.264 And you have to keep it in sync with your skeletal muscle system. 00:36:03.404 --> 00:36:06.944 And I think it's still a mystery. You know, the relationship between, I can't, I mean, 00:36:07.424 --> 00:36:11.124 we have to be careful because we don't have any information about how that comparator 00:36:11.124 --> 00:36:16.264 works, how it's being trained up, and whether or not wake movements are part 00:36:16.264 --> 00:36:19.324 of the training process or whether twitching is doing the work for that. 00:36:19.544 --> 00:36:21.384 We still don't know the answer to that question. 00:36:21.764 --> 00:36:25.504 And we're pretty far from answering it probably. But now you did mention that's 00:36:25.504 --> 00:36:26.484 obviously complex spikes. 00:36:26.664 --> 00:36:31.404 There'll be a signature of inferior olive involvement and also changes in the 00:36:31.404 --> 00:36:35.204 simple spikes of Purkinje cells, which would suggest that we have mossy fiber 00:36:35.204 --> 00:36:39.464 inputs to the Purkinje cells also conveying information on the twitch. 00:36:39.604 --> 00:36:42.444 So how would, should we, now the inferior olive is usually seen as conveying 00:36:42.444 --> 00:36:45.284 error signals and driving learning in the cerebellar cortex. 00:36:45.284 --> 00:36:49.364 So that would mean that we actually have two inputs coming from the red nucleus-induced 00:36:49.364 --> 00:36:53.084 twitches into the cerebellum, and one is in, let's say, a sensory state, 00:36:53.304 --> 00:36:54.724 and the other one is more an error. 00:36:55.044 --> 00:37:00.284 So could we interpret this as the first one reflecting the initiation of the 00:37:00.284 --> 00:37:05.804 twitch, and the second one reflecting, let's say, the recurrent feedback we're 00:37:05.804 --> 00:37:09.304 getting from the execution of the twitch, driving, for example, the error signal? 00:37:09.664 --> 00:37:14.244 Or you would, at this point, not try to differentiate so specifically? 00:37:15.124 --> 00:37:18.884 Things get really tricky when you start. So the concept that the inferior olive 00:37:18.884 --> 00:37:21.984 is computing error signals comes from work in adults. 00:37:22.344 --> 00:37:26.024 And it's possible that that concept can be imported. 00:37:27.202 --> 00:37:31.542 You know, with precision into development. But it's also possible that the role 00:37:31.542 --> 00:37:33.382 of the inferior olive changes developmentally. 00:37:33.682 --> 00:37:36.882 So it's conceivable, I think, in our mind, that really what's happening with 00:37:36.882 --> 00:37:40.862 the inferior olive is you're still setting up the topography of the cerebellum. 00:37:41.002 --> 00:37:44.442 So that what you're getting is a signal from the inferior olive, 00:37:44.602 --> 00:37:49.982 whose only purpose at that age is to line up with the sensory input that's coming 00:37:49.982 --> 00:37:51.842 from the twitching limb or whatever. 00:37:52.162 --> 00:37:56.042 And then you have a convergent input that allows a cell in the cerebellum to 00:37:56.042 --> 00:38:00.522 say, oh, I just got a signal that comes from this part of the red nucleus and 00:38:00.522 --> 00:38:02.442 this part of the body, and they're all linked together. 00:38:02.682 --> 00:38:07.882 If that linkage process is what development is about, that could be it. 00:38:08.142 --> 00:38:11.982 And remember, the cerebellum at these ages is extremely depleted in terms of 00:38:11.982 --> 00:38:15.722 its complexity. There are no granule cells or parallel fibers that have yet emerged. 00:38:16.022 --> 00:38:19.582 And you have this opportunity to simply converge inputs. 00:38:20.182 --> 00:38:23.222 And that may be the functional role of the inferior olivate at this age. 00:38:23.222 --> 00:38:26.042 But it's interesting because it might actually also help the cerebellum, 00:38:26.062 --> 00:38:31.362 which is in that stage also developing very rapidly, to obey a certain somatotopy. 00:38:31.762 --> 00:38:35.382 Because this is actually one of the characteristic features of the cerebellum 00:38:35.382 --> 00:38:38.962 and the climbing fiber inputs in it, that you have multiple somatotopic maps 00:38:38.962 --> 00:38:41.562 of the body that, of course, you have to lay down in some way. 00:38:41.722 --> 00:38:44.962 And your twitching signals might be essential to actually get that done. 00:38:45.102 --> 00:38:47.722 That's exactly what we think is the key about that. 00:38:47.962 --> 00:38:51.182 Whether there are other functions about the inferior olive or any part of the 00:38:51.182 --> 00:38:55.062 system that we're missing by virtue of our methods or anything else, 00:38:55.182 --> 00:38:58.442 you know, that's something we have to take care and make sure about. 00:38:58.642 --> 00:39:02.442 But as of, you know, given our methods and given what we've seen so far, 00:39:02.702 --> 00:39:07.842 we think it's mostly for somatotopic organization at this stage. 00:39:08.022 --> 00:39:12.522 Okay. But that would imply that then for adults that have a somatotopic organized cerebellum. 00:39:13.240 --> 00:39:17.140 The twitching signals would not be really having a strong impact on cerebellum anymore. 00:39:17.640 --> 00:39:22.200 Is that the case? Well, the short answer is nobody knows. 00:39:22.500 --> 00:39:29.420 And the longer answer is that you not only have to develop and refine systems, 00:39:29.660 --> 00:39:31.760 but you have to maintain them and you have to repair them. 00:39:32.020 --> 00:39:35.980 And so it's conceivable that what happens in adulthood is maintenance and repair. 00:39:36.300 --> 00:39:39.520 And it also could be that when we do certain types of skill learning, 00:39:39.700 --> 00:39:44.120 learning to play a piano, for example, that you could actually engage some of 00:39:44.120 --> 00:39:48.280 these mechanisms again in distinct ways. Has this ever been looked at? 00:39:48.580 --> 00:39:51.420 Absolutely not. So we do not know the answer to that. 00:39:51.560 --> 00:39:54.100 It's conceivable that twitches are important for early development. 00:39:54.220 --> 00:39:56.960 They go away and they're not heard from again from a functional perspective. 00:39:57.360 --> 00:40:02.720 But it's also possible that we've been missing out on a very important aspect of adult function. 00:40:03.080 --> 00:40:07.260 So twitches could have multiple functions, I think you're saying that. 00:40:07.440 --> 00:40:11.060 I mean, if we If we go back to our robotics analogy, then I think you've already 00:40:11.060 --> 00:40:16.400 mentioned the fact that a twitch could help me keep my joints free so that I 00:40:16.400 --> 00:40:17.380 don't use my arm for a while. 00:40:17.440 --> 00:40:20.460 It could seize up, so a twitch could give me some flexibility. 00:40:21.480 --> 00:40:26.100 A twitch could let me know that my control system is working. 00:40:26.360 --> 00:40:29.460 You know, sort of, I need to know that when I command an instruction, 00:40:29.700 --> 00:40:30.820 the arm will actually move. 00:40:30.980 --> 00:40:33.020 And, you know, we do this in the lab all the time. You know, 00:40:33.040 --> 00:40:37.480 can I still move his fingertip? We send a small movement and it works. 00:40:38.720 --> 00:40:41.800 Something like a twitch could allow you to configure the 00:40:41.800 --> 00:40:44.760 pattern generation system and you know 00:40:44.760 --> 00:40:48.180 in terms of where the primitives come from they have to self-assemble in 00:40:48.180 --> 00:40:51.200 some way and they could assemble by making you 00:40:51.200 --> 00:40:56.420 know just fire a few neurons you get some movement and then you you're you figure 00:40:56.420 --> 00:40:59.520 out that if you fire these groups of neurons together you get a more complex 00:40:59.520 --> 00:41:05.400 movement or two limbs move together that sort of thing so uh and that uh in 00:41:05.400 --> 00:41:08.740 robotics people have used this sort of motor babbling, 00:41:09.586 --> 00:41:12.606 to try and work out how to control your body. 00:41:12.746 --> 00:41:18.546 So you can learn to move a robot arm to a point in space by sending different 00:41:18.546 --> 00:41:23.306 random commands to the joints of the arm and seeing what happens and building up a map that way. 00:41:24.306 --> 00:41:29.746 And then I think you were emphasizing in your talk about twitches generating 00:41:29.746 --> 00:41:32.226 sensory feedback to the brain. 00:41:32.346 --> 00:41:37.806 And then that's another, I mean, that's similar in a way to this learning how to control the arm. 00:41:37.886 --> 00:41:40.846 But would you say it's the same thing or another thing i 00:41:40.846 --> 00:41:43.726 think it's in the same ballpark i think that we're talking about a similar class 00:41:43.726 --> 00:41:46.606 of of ideas what you know the motor babbling 00:41:46.606 --> 00:41:49.806 idea i think is is a it's a form of exploration yeah 00:41:49.806 --> 00:41:53.546 and i'm talking here about using twitching as a form of exploration too the 00:41:53.546 --> 00:41:57.826 details may or may not be critical you know so the the but you know we're in 00:41:57.826 --> 00:42:03.106 a robot system you have a much more you it's a much more low noise system right 00:42:03.106 --> 00:42:07.366 and typically compared to a biological system is Is that a fair thing to say? 00:42:07.746 --> 00:42:10.946 If you were sensory input? Yeah, I would say so. Okay. You know, 00:42:10.986 --> 00:42:14.546 so the challenge for a biological system is to reduce the noise. 00:42:14.846 --> 00:42:18.406 You have multiple modalities, you know, multiple, so many peripheral receptors, 00:42:18.566 --> 00:42:20.386 so many different things happening at the same time. 00:42:20.846 --> 00:42:24.966 Everything, all these different things you need to organize in order to figure out what's going on. 00:42:25.206 --> 00:42:29.426 And of course, you can program the motor babbling to be just move this arm in this way. 00:42:29.626 --> 00:42:33.086 And it could be that the biological system has to solve that problem differently, 00:42:33.246 --> 00:42:35.506 perhaps by going into a state like sleep. 00:42:36.506 --> 00:42:41.126 But I don't see any reason why you can't model that very idea in a robotic situation. 00:42:41.146 --> 00:42:44.446 Well, I know every robot has a massive problem always with calibration. 00:42:44.786 --> 00:42:49.266 Before you do anything, always first, okay, we have to calibrate that the robot 00:42:49.266 --> 00:42:54.106 really knows where its limbs are because otherwise things will go dramatically wrong, right? 00:42:54.186 --> 00:42:57.826 So you spend a lot of time on these calibration issues, which are often taken 00:42:57.826 --> 00:43:00.386 for granted and not really seen as part of the solution. 00:43:00.786 --> 00:43:04.746 But what you're describing here is also the brain's calibration system to stay 00:43:04.746 --> 00:43:06.386 synchronized with its body. 00:43:07.146 --> 00:43:11.386 I mean, my idea of a perfect world is where roboticists take these ideas seriously, 00:43:11.526 --> 00:43:15.166 sort of along the lines of what I was... My perfect world was very different, Mark. 00:43:16.346 --> 00:43:21.026 Well, I was a morbid idealist when I was a child, but now I care about this. 00:43:21.066 --> 00:43:22.286 I'm one thing only, you know. 00:43:22.786 --> 00:43:27.206 Life has changed a lot. That's right. I've become very narrow in my perfection ideals. 00:43:28.586 --> 00:43:31.506 He just wants obedient roboticists, you know. 00:43:31.566 --> 00:43:34.606 Yes, my idea of a perfect world is where roboticists take these ideas seriously. 00:43:34.606 --> 00:43:37.666 But seriously, I mean, it would become pretty close. 00:43:41.506 --> 00:43:46.806 So we have some clear ideas. Also, we have the beginnings of a circuit diagram, 00:43:47.086 --> 00:43:49.166 if you want, how these signals play out. 00:43:49.826 --> 00:43:54.686 But now what you also showed, which is really very curious, is that you really 00:43:54.686 --> 00:43:58.486 can see a very strong difference of how these twitch signals might actually 00:43:58.486 --> 00:44:03.206 impact thalamus, cortex, and hippocampus in wakefulness and sleep. 00:44:03.206 --> 00:44:07.246 And what you showed there, which I found very surprising, is indeed also these 00:44:07.246 --> 00:44:13.326 twitch signals, you can show like very strong responses in thalamus and cortex. 00:44:13.706 --> 00:44:17.026 So how dominant are those signals? 00:44:18.666 --> 00:44:23.886 Very dominant. it. The signals that we see in twitching in a cortex and in the 00:44:23.886 --> 00:44:28.386 parts of thalamus we've looked at, which are the parts of thalamus that process sensory input, 00:44:28.726 --> 00:44:34.066 they are arguably more activated during REM sleep than they are during any other 00:44:34.066 --> 00:44:35.566 stage of these animals' lives. 00:44:35.706 --> 00:44:38.866 Now, again, we are not looking at animals freely moving in a nest. 00:44:39.326 --> 00:44:43.006 And I think it's very important to say that because obviously there's a lot 00:44:43.006 --> 00:44:45.966 of things that go on in an animal that's engaging in its environment in in a 00:44:45.966 --> 00:44:48.946 more natural way than we are able to pick up at this stage. 00:44:49.086 --> 00:44:52.726 But nonetheless, in an animal under our conditions, 00:44:53.426 --> 00:44:58.886 the activity that we see is so precisely associated with twitching and so shut 00:44:58.886 --> 00:45:06.326 off during wakefulness that that gave us the clue to start thinking about this 00:45:06.326 --> 00:45:07.946 coronary discharge situation. 00:45:08.066 --> 00:45:12.226 So if we had gone immediately to a more naturalistic setting, 00:45:12.226 --> 00:45:15.186 we would have never seen the pattern of activity 00:45:15.186 --> 00:45:18.206 that we saw and we would have never been able to dissect out 00:45:18.206 --> 00:45:21.126 this aspect of the circuit but the thalamus and 00:45:21.126 --> 00:45:25.106 cortex are very different i'm talking about sensory motor cortex we've recorded 00:45:25.106 --> 00:45:29.246 from visual cortex and it has a lot of the same activity patterns but in that 00:45:29.246 --> 00:45:33.966 situation it's driven by retinal waves and the retinal waves are not occurring 00:45:33.966 --> 00:45:38.406 during sleep or wake they're just they're happening on their own cycle and so there 00:45:38.486 --> 00:45:40.726 are parts of development that have no tie. 00:45:41.506 --> 00:45:43.726 To the sleep-wake cycle, as far as we can tell. 00:45:43.866 --> 00:45:49.666 We do see activity in visual cortex that is independent of the retinal input. 00:45:50.591 --> 00:45:54.351 That is associated with sleep that we haven't, that we're still working on. 00:45:54.351 --> 00:45:56.791 But what you essentially see is in sleep, if I have a twitch, 00:45:57.071 --> 00:46:02.231 you will see a spindle-like associated response with a very short latency after 00:46:02.231 --> 00:46:04.131 the twitch in thalamus and cortex. 00:46:04.491 --> 00:46:07.831 Right. About 100, about 100 milliseconds, give or take. Okay. 00:46:07.951 --> 00:46:13.151 Yeah. So, but that, how do you interpret that spindle response? 00:46:13.391 --> 00:46:15.011 This is low frequency, high amplitude. 00:46:15.531 --> 00:46:19.271 Yeah. So what's it doing? Well, you know, in the adult literature, 00:46:19.291 --> 00:46:22.171 people talk about spindles playing an important role in memory consolidation. 00:46:22.511 --> 00:46:25.471 But here we're talking about movement-related activity. 00:46:25.831 --> 00:46:30.131 It appears that what makes cortex homogeneous from a functional perspective 00:46:30.131 --> 00:46:33.491 is it doesn't matter what kind of input you have to the cortex, 00:46:33.771 --> 00:46:35.071 it's going to show a spindle. 00:46:35.071 --> 00:46:41.831 The first thing it shows is this oscillation, this little reverberation in the circuit. 00:46:42.131 --> 00:46:45.151 But it is accompanied, certainly we've seen it in older ages, 00:46:45.291 --> 00:46:47.891 by unit activity, by actual neuronal firing. 00:46:48.051 --> 00:46:50.351 So it's not just the local field potential. 00:46:50.571 --> 00:46:53.451 You also have the action potentials accompanying it. 00:46:54.651 --> 00:46:58.751 But how the spindle plays a role in actually altering circuitry, 00:46:58.811 --> 00:47:01.971 we don't know. Would you see this as a reset signal? 00:47:02.731 --> 00:47:07.351 Because basically what's happening, if you pump so much energy into a small 00:47:07.351 --> 00:47:10.971 volume of cortex, you will entrain all the neurons in that volume. 00:47:11.771 --> 00:47:15.631 And whatever these guys are integrating, you really reset that. It's gone. 00:47:16.131 --> 00:47:20.451 Right? You don't mean resetting in the oscillation sense of resetting. 00:47:20.471 --> 00:47:24.151 You mean… Well, you actually, you're just resetting all these neurons to the 00:47:24.151 --> 00:47:25.391 same state, essentially, right? 00:47:25.431 --> 00:47:27.871 It's possible. We've never, I mean, we don't have any evidence for that, 00:47:27.911 --> 00:47:28.751 something like that yet. 00:47:28.751 --> 00:47:31.531 At it and but one thing that you see early in development that's so 00:47:31.531 --> 00:47:34.531 striking is that the the cortical activity is so 00:47:34.531 --> 00:47:37.391 quiet i mean it's like it's like the stillest of 00:47:37.391 --> 00:47:41.491 water and then a twitch happens and it's just a little ripple in the surface 00:47:41.491 --> 00:47:45.691 and then it goes away back to you know and if you record we what we need to 00:47:45.691 --> 00:47:49.911 do is to sort of get what you're asking about is really record from a much larger 00:47:49.911 --> 00:47:54.831 population of neurons to get a better sense of what the population activity of those neurons are. 00:47:55.011 --> 00:48:00.711 And there's been some work by Yuri Busaki's group on that going back 10 years, 00:48:00.851 --> 00:48:05.531 but there needs to be more of that sort of work to really see what's going on more dynamically. 00:48:05.531 --> 00:48:12.251 But now the, if, because I think for your model to work, I think it's. 00:48:12.710 --> 00:48:17.770 I would expect that you want to show is that I trigger my spindle, my twitch, 00:48:17.990 --> 00:48:24.290 I get a recurrent response via spindle, and now learning something at the cortical 00:48:24.290 --> 00:48:29.930 level because I'm actually wiring in or rewiring my cortical control over that 00:48:29.930 --> 00:48:31.730 little set of muscle fibers. 00:48:32.110 --> 00:48:35.230 Yes. Well, that's one dimension of plasticity that may be important. 00:48:35.370 --> 00:48:37.750 But another dimension, and that's what I tried to highlight at the end, 00:48:37.810 --> 00:48:42.290 was just that cascade of activity from area to area to area to area. 00:48:42.710 --> 00:48:46.950 And so what you may actually be doing, and this could be one of many possible functions, 00:48:47.150 --> 00:48:51.910 is that you're really connecting up these individual pairs of areas so that 00:48:51.910 --> 00:48:56.070 an area fires and then a very high probability of a neuron in the next area, 00:48:56.210 --> 00:48:59.530 that is what allows for the sort of Hebbian process of saying, 00:48:59.610 --> 00:49:02.730 you know, now I'm talking to you and we're part of the same system. 00:49:02.730 --> 00:49:06.590 We belong to the same club and the, and you, you don't belong to my club. 00:49:06.690 --> 00:49:09.310 You're, you're not part of the right forelimb. You're part of the right hind 00:49:09.310 --> 00:49:12.390 limb or, or you're just another part of the body and I don't care about you. 00:49:12.470 --> 00:49:15.170 So if you're, you know, the process of developing these systems, 00:49:15.250 --> 00:49:18.250 these topographic systems involves not only saying what, what, 00:49:18.310 --> 00:49:20.710 who, who I belong to, but who doesn't belong to me. 00:49:20.870 --> 00:49:24.890 And that process across areas may be just as important as what's happening within 00:49:24.890 --> 00:49:27.490 a given area. Okay. Does that make sense? 00:49:28.770 --> 00:49:31.570 Sure. Sure, because what you're saying is, look, what I do now, 00:49:31.650 --> 00:49:35.410 I'm twitching, I generate a strong response in my thalamus. 00:49:36.430 --> 00:49:40.730 This is now driving cortical volume. And now I get some ripple going through 00:49:40.730 --> 00:49:47.710 my cortical network, which allows neurons associated with that twitch to be linked together. 00:49:47.850 --> 00:49:50.650 Exactly. I think that's a perfect extension. Yeah, absolutely. 00:49:50.650 --> 00:49:56.090 And however, the alternative could be to say, well, when you twitch, just ignore it. 00:49:56.830 --> 00:50:00.490 Reset the cortex, whatever's going to happen, we're going to ignore it because 00:50:00.490 --> 00:50:02.470 we're just twitching. It's completely meaningless. 00:50:03.090 --> 00:50:06.650 So how can you refute that interpretation? I can't refute it. 00:50:06.730 --> 00:50:12.130 I can only use, I mean, you know, like I said, I mean, you know, 00:50:12.130 --> 00:50:15.370 I've been trying to be skeptical about the possible, you know, 00:50:15.390 --> 00:50:18.550 there's always the possibility that a system does things and it has no functional 00:50:18.550 --> 00:50:20.670 importance whatsoever. I mean, you have to keep that. 00:50:21.370 --> 00:50:24.750 Perhaps that has to be your null hypothesis all the time. And that had to be 00:50:24.750 --> 00:50:26.490 mine, you know, until very recently. 00:50:26.710 --> 00:50:30.830 And what convinced me that that wasn't the case was, first, the fact that Twitch-related 00:50:30.830 --> 00:50:34.630 information is getting into the brain and Wake-related information is not. 00:50:34.830 --> 00:50:39.610 But also, secondly, the sheer enormity of the activity we're talking about here. 00:50:39.610 --> 00:50:43.610 So, you know, there's a big emphasis in psychology and neuroscience about the 00:50:43.610 --> 00:50:47.930 quantity of input being an important player in developing systems. 00:50:48.430 --> 00:50:52.110 And I don't see how you can avoid the fact that hundreds of thousands of twitches 00:50:52.110 --> 00:50:58.210 are happening every day and activity is happening throughout the entire brain that is so profound. 00:50:59.198 --> 00:51:02.578 It would be extraordinary to me if this was not functionally important. 00:51:02.798 --> 00:51:06.458 If the nervous system could actually ignore all of that activity, 00:51:06.898 --> 00:51:09.158 that would seem to be unprecedented. 00:51:09.938 --> 00:51:15.298 And so it's not just activity, it's highly structured activity with real information content. 00:51:15.838 --> 00:51:19.858 It seems to me the brain is in the process of making sense of information, not ignoring it. 00:51:19.998 --> 00:51:25.198 So I just would be stunned if at this point it would be… Perhaps some analysis 00:51:25.198 --> 00:51:28.558 of the spatiotemporal patterns would help that. 00:51:28.558 --> 00:51:31.598 I don't know how far you've gone down this route, but, you know, for instance, 00:51:31.918 --> 00:51:38.598 you might hope to see that all the different potential ways in which you could 00:51:38.598 --> 00:51:45.678 move a particular muscle would be explored over a period of time rather than just one. 00:51:45.678 --> 00:51:51.238 Because you perhaps want to imagine that your motor maps and cortex are seeing 00:51:51.238 --> 00:51:54.658 the full range of potential ways of controlling that system. 00:51:54.858 --> 00:51:58.258 And maybe also to say to it, look, you've been doing this action a lot today. 00:51:58.698 --> 00:52:02.858 Remember there are these other actions that you could do and make sure you retain space for those. 00:52:03.338 --> 00:52:06.778 I think that's a great point, and we have made some inroads on that issue. 00:52:07.578 --> 00:52:12.598 We've been doing some filming of rat pups when they are in a harness, 00:52:12.638 --> 00:52:13.698 so we're filming them from below. 00:52:13.698 --> 00:52:16.818 And we're looking at if you imagine looking from 00:52:16.818 --> 00:52:20.038 below of a of a the tip of a limb that limb 00:52:20.038 --> 00:52:22.758 is going to occupy different parts in a two-dimensional space that you 00:52:22.758 --> 00:52:27.098 can see from below and what is very striking that you see is that when the animals 00:52:27.098 --> 00:52:31.578 wake up and they're kicking their their movements as you follow them you know 00:52:31.578 --> 00:52:36.298 represents a very small part of space compared to the twitches themselves which 00:52:36.298 --> 00:52:42.538 are filling up almost like a spherical and elliptic elliptical region around that mid-rest point. 00:52:42.938 --> 00:52:46.938 And that tells me, along the lines of what you're saying, that these animals 00:52:46.938 --> 00:52:50.698 are really exploring the full range of biomechanical possibilities of their limbs. 00:52:50.978 --> 00:52:54.798 Well, there's another aspect to this, actually, which you often ignore. 00:52:54.898 --> 00:52:58.038 Often we think about our bodies as if it's a robot, right? 00:52:58.118 --> 00:53:01.318 But that's actually not really the case, because once you drive the same muscle 00:53:01.318 --> 00:53:06.358 fiber frequently, you deplete it of glycogen, it will start to get fatigued, 00:53:06.378 --> 00:53:10.198 and you must start to recruit other muscle fibers to maintain that same movement. 00:53:10.198 --> 00:53:13.218 I don't know if you ever ran a marathon, but you'll discover how many different 00:53:13.218 --> 00:53:16.698 gates you can generate if you run a marathon, at least at a decent speed. 00:53:17.038 --> 00:53:23.598 So the point here is, and this might be also an exploration of alternative, 00:53:23.778 --> 00:53:30.178 let's say, muscle fiber groups that can be recruited into a functional unit. 00:53:30.858 --> 00:53:35.238 So the point is, if you would only depend on what you really use during the day, you, 00:53:35.783 --> 00:53:40.003 You might also, in some sense, set yourself up for a fall because you become 00:53:40.003 --> 00:53:44.243 highly specialized and you cannot go for, let's say, alternative movement patterns 00:53:44.243 --> 00:53:48.143 anymore, recruiting associated or alternative muscle fiber groups. 00:53:48.343 --> 00:53:51.343 I think that's a great point. And there are similar phenomena where you could, 00:53:51.483 --> 00:53:54.643 in addition to what you're talking about of depletion, but also if you put a 00:53:54.643 --> 00:53:59.043 restriction on somebody's movements and how quickly people can then go to an 00:53:59.043 --> 00:54:00.943 alternative way of doing things. 00:54:00.943 --> 00:54:03.483 You know, you stick a cork in your mouth and you can figure out another way 00:54:03.483 --> 00:54:07.023 to voice, you know, what you want to talk about. Shall we try that? 00:54:08.783 --> 00:54:15.603 So I think the online motor plasticity that we have is extraordinary. 00:54:15.723 --> 00:54:16.943 And where does that come from? 00:54:17.223 --> 00:54:20.903 Even when you have never experienced something before, you very quickly can 00:54:20.903 --> 00:54:23.363 figure out how to get around that barrier. 00:54:23.643 --> 00:54:26.703 And I think that could be, you know. Right, because imagine you would have to 00:54:26.703 --> 00:54:31.683 figure out at that point in time how to innervate your muscle in order to drive 00:54:31.683 --> 00:54:34.283 it in some alternative pattern. Yes. 00:54:36.103 --> 00:54:39.083 I think when we were talking earlier, you mentioned that you thought it would 00:54:39.083 --> 00:54:40.623 be difficult to block twitches. 00:54:41.283 --> 00:54:45.523 So some of the obvious experiments where you prevent animals having twitches 00:54:45.523 --> 00:54:49.163 and then you look for deficits are not going to be easy to do. 00:54:49.863 --> 00:54:55.583 But are there other experiments that you're trying to do which will more directly 00:54:55.583 --> 00:55:01.043 show a causal link between the twitch and some of these benefits that you think are going to have. 00:55:01.163 --> 00:55:04.343 This has been an incredibly frustrating part of doing this work. 00:55:04.483 --> 00:55:07.503 I mean, you know, for the people who are looking at the development of the visual 00:55:07.503 --> 00:55:09.923 system and you have retinal wave activity. 00:55:11.037 --> 00:55:16.097 The retina wave activity, this is at a time of an animal's life when they have no wake. 00:55:16.717 --> 00:55:21.037 They're not able to receive light. So it's just retina, it's spontaneous activity, 00:55:21.137 --> 00:55:22.197 it has nothing to do with light. 00:55:22.857 --> 00:55:28.397 And I envy them the ability to stick a needle in the eye, sorry that sounds 00:55:28.397 --> 00:55:32.657 a little gross, and inject a drug that simply blocks all that activity and look at the consequences. 00:55:33.057 --> 00:55:37.017 We can't do that. I mean, first of all, what we're looking at is a sensory motor 00:55:37.017 --> 00:55:41.017 system that has these loops. loops and we're looking at a system that is specific 00:55:41.017 --> 00:55:43.937 to sleep, whereas retinal wave activity is not. 00:55:44.317 --> 00:55:50.917 So we have a double problem that, uh, that people working on pure sensory systems just don't have. 00:55:51.137 --> 00:55:56.197 And that has proven to be a, uh, an incredible barrier to nailing down something. 00:55:56.357 --> 00:55:59.817 So instead what we've done is we've relied on converging evidence and we've 00:55:59.817 --> 00:56:02.777 tried to look at, you know, sort of circling the drain of all, 00:56:02.777 --> 00:56:07.177 of all the various things that we might predict based upon, you know, our, our hypotheses. 00:56:07.437 --> 00:56:11.377 And we are trying to get at this issue and we have tried to use things like 00:56:11.377 --> 00:56:15.257 optogenetics, but there are limits, uh, for our system and using it. 00:56:15.257 --> 00:56:18.997 I won't go into the details, but there are, um, it's not as easy as it is, 00:56:19.037 --> 00:56:20.877 for example, if you're doing adult work. Right. 00:56:21.517 --> 00:56:24.137 So, um, I never thought I would say, you know, optogenetics is easy, 00:56:24.197 --> 00:56:27.577 but, you know, but it's relatively harder to do in an animal that, 00:56:27.577 --> 00:56:28.997 and that's, uh, very young. 00:56:29.437 --> 00:56:34.877 So So there have been these impediments to solving, you know, 00:56:34.897 --> 00:56:36.957 this problem of function once and for all. 00:56:38.317 --> 00:56:42.817 But I think we're going to get there. We have ideas. We have certain sorts of 00:56:42.817 --> 00:56:46.057 conditioning or learning paradigms that we've thought about being able to employ. 00:56:46.277 --> 00:56:51.317 And I think I'm hopeful in the next two or three years we'll nail it down. And is there some... 00:56:52.654 --> 00:56:56.194 Follow through or crossover into sort of treatments are 00:56:56.194 --> 00:56:59.154 there people for whom you know maybe kicking more 00:56:59.154 --> 00:57:02.174 in their sleep would well you know some benefit 00:57:02.174 --> 00:57:05.414 so we just got funded by the gates foundation to to branch 00:57:05.414 --> 00:57:08.394 out and to start looking at uh human infant 00:57:08.394 --> 00:57:12.874 development and we want to know first of all you know how much do human infants 00:57:12.874 --> 00:57:18.414 twitch and also are there individual differences and ultimately the reason why 00:57:18.414 --> 00:57:23.714 uh the the whole point of this particular project um was to conceive of using 00:57:23.714 --> 00:57:27.694 twitching as an early and sensitive indicator of developmental disorders. 00:57:28.474 --> 00:57:33.394 A lot of these psychiatric disorders, some might argue every psychiatric disorder 00:57:33.394 --> 00:57:35.954 or developmental disorder, has a motor component to it. 00:57:36.134 --> 00:57:39.154 Sometimes the motor components are enormous and have been largely ignored. 00:57:39.554 --> 00:57:42.774 Autism has a huge motor component. Schizophrenia has a huge motor component. 00:57:43.014 --> 00:57:46.274 And the question is, where do these problems come from? Well, 00:57:46.294 --> 00:57:47.794 if they start as developmental problems, 00:57:48.054 --> 00:57:52.874 then we should know what's going on developmentally, And it's conceivable that 00:57:52.874 --> 00:57:56.894 how the motor system develops, which is so important to the problems that autistic 00:57:56.894 --> 00:57:59.094 kids have or schizophrenics. 00:57:59.154 --> 00:58:03.494 I mean, if you understood whether or not there are problems in the early development 00:58:03.494 --> 00:58:07.314 of the sensory motor system, the early organization of corollary discharge systems, 00:58:07.454 --> 00:58:12.994 that we might gain a foothold either into predicting and then ultimately treating, 00:58:13.254 --> 00:58:17.434 better treating these sorts of problems before they become full-blown. 00:58:17.434 --> 00:58:22.574 That would be the, you know, the pie in the sky kind of dream for this sort of thing. 00:58:23.034 --> 00:58:26.014 And that's exactly what we're trying to do. 00:58:26.474 --> 00:58:30.854 So individual differences could provide a really important clue to that sort of thing. 00:58:30.934 --> 00:58:37.394 And I talked a little bit today about autism and the role that the cerebellar system may have in that. 00:58:37.394 --> 00:58:43.794 And so, you know, we don't pay a lot of attention to how healthily our infants 00:58:43.794 --> 00:58:49.354 are sleeping, you know, but the environment for sleep could be a critical determining 00:58:49.354 --> 00:58:50.774 factor for a lot of these things. 00:58:50.994 --> 00:58:55.094 Now, we have quite an interest in stroke because we think that if we're going 00:58:55.094 --> 00:58:59.174 to have any impact in the neuropathology, stroke should be the first one because 00:58:59.174 --> 00:59:01.234 it's the simplest one, right? Having a hole in your brain. 00:59:01.754 --> 00:59:05.854 But now in stroke patients, would you see more twitching? 00:59:06.869 --> 00:59:09.069 So we have a study that we're starting, that we've been starting. 00:59:09.269 --> 00:59:11.949 We're waiting for our first patient in humans. 00:59:12.349 --> 00:59:15.489 We're aiming to look at their sleep patterns immediately post-stroke. 00:59:16.369 --> 00:59:19.609 There are two ways to think about this. One would be that, you know, 00:59:19.649 --> 00:59:22.149 one reason why stroke is so problematic, 00:59:22.489 --> 00:59:26.069 you know, massive cortical stroke and very problematic paresis, 00:59:26.089 --> 00:59:31.509 as you know, the one way to think about it is that we're out of luck because we're older. 00:59:31.749 --> 00:59:34.789 I mean, I'm not talking here about perinatal stroke, just adult stroke. 00:59:34.789 --> 00:59:39.169 And we're out of luck because we don't have access to the same mechanisms as 00:59:39.169 --> 00:59:40.569 adults as we did when we were infants. 00:59:41.189 --> 00:59:44.869 You know, everybody knows that infants are able to recover from these things 00:59:44.869 --> 00:59:47.229 much more than adults can. 00:59:47.449 --> 00:59:50.729 Well, why can infants recover so much more quickly? I would argue that there 00:59:50.729 --> 00:59:51.449 are a variety of reasons. 00:59:51.709 --> 00:59:54.949 One of them could be because of the nature of how they're still in the process 00:59:54.949 --> 00:59:57.129 of developing these systems. They're still more plastic. 00:59:58.089 --> 01:00:02.049 The other possibility though though, that I think needs to be looked at is the 01:00:02.049 --> 01:00:10.269 one where you're actually able to recruit these older mechanisms under conditions of disrupted maps. 01:00:10.689 --> 01:00:15.229 So now stroke may be too high up in the hierarchy to recruit that. 01:00:15.369 --> 01:00:19.109 So it's possible. What happens when you have amputation and you have to learn 01:00:19.109 --> 01:00:22.289 how to use your remaining arm in a functionally new way? 01:00:22.329 --> 01:00:25.549 Or what happens after peripheral nerve damage where you've lost some control 01:00:25.549 --> 01:00:27.429 and those nerves are growing back? 01:00:27.429 --> 01:00:30.789 Under those conditions, it's conceivable that the nervous system is actually 01:00:30.789 --> 01:00:35.389 able to detect a very dramatic change in the relationship between the peripheral 01:00:35.389 --> 01:00:40.229 part of your body, your limbs, and your brain, and could re-engage the process 01:00:40.229 --> 01:00:41.669 of spontaneous activity. 01:00:42.029 --> 01:00:46.369 And what if it's possible that some of us are better able to engage that process than others of us? 01:00:46.429 --> 01:00:49.589 Then you could have individual differences in recovery from these sorts of things. 01:00:49.589 --> 01:00:53.509 Those are the kinds of questions I want to address because if, 01:00:53.509 --> 01:00:58.849 you know, even if it's partially right, there could be a way eventually to use, 01:00:58.989 --> 01:01:01.669 just like people are recording from, 01:01:01.829 --> 01:01:04.869 neurosurgeons are recording in many centers now across the country, 01:01:04.929 --> 01:01:10.969 including at the University of Iowa, in epileptic patients with chronic electrodes in the cortex. 01:01:10.969 --> 01:01:15.109 Cortex, it would be possible ultimately to implant electrodes into the brainstem 01:01:15.109 --> 01:01:19.849 and to stimulate what's happening in early development and to basically re-bootstrap 01:01:19.849 --> 01:01:22.129 that system from the inside out. 01:01:22.269 --> 01:01:25.849 So if we could recruit twitching, if twitching turns out to be important, 01:01:26.069 --> 01:01:30.869 it's not crazy science fiction to think that you could put in electrodes into 01:01:30.869 --> 01:01:36.469 the brainstem and stimulate different parts of it and reinvigorate the development of the system. 01:01:36.589 --> 01:01:38.889 But how about starting with just direct muscle stimulation? 01:01:39.409 --> 01:01:42.829 Well, that might work to some extent. I mean, we saw from Brian Kolb's talk 01:01:42.829 --> 01:01:47.069 that peripheral stimulation through stroking can have an important effect on plasticity. 01:01:47.269 --> 01:01:52.309 But I think that if we're right about the role that twitching plays as a self-generated 01:01:52.309 --> 01:01:55.969 movement, it may be important for the nervous system to both produce the movement 01:01:55.969 --> 01:01:57.429 and to get the feedback itself. 01:01:58.009 --> 01:01:59.869 Still a very interesting open question. 01:02:01.810 --> 01:02:06.650 So another issue that I was curious about, so if we're now thinking about using 01:02:06.650 --> 01:02:12.330 twitching to set up our control system for motor control, another important 01:02:12.330 --> 01:02:14.550 aspect of motor control is its rhythmicity. 01:02:14.790 --> 01:02:20.270 There are these ideas around different people that also motor control is very 01:02:20.270 --> 01:02:24.850 much segmented in time at a certain frequency, let's say 10 hertz or what have you. 01:02:25.270 --> 01:02:30.550 Would you see similar kinds of patterns or patterning in how twitches are generated? 01:02:31.810 --> 01:02:35.330 And how does that vary over development, if at all? 01:02:36.690 --> 01:02:41.650 So we're looking at that issue right now, and we're still analyzing data. 01:02:42.330 --> 01:02:46.650 We're very interested now in a variety of different rhythmic patterns that we see. 01:02:47.630 --> 01:02:52.250 And what we're primarily seeing as of right now at these particular ages and 01:02:52.250 --> 01:02:55.250 in the parts of the brain we're looking at is that the most rhythmic activity 01:02:55.250 --> 01:02:57.130 occurs when the animal is not moving at all. 01:02:57.130 --> 01:03:00.790 And then what happens when the animal starts to twitch is that those rhythmic 01:03:00.790 --> 01:03:05.470 patterns disappear and then the animal stops twitching or stops moving and the 01:03:05.470 --> 01:03:07.910 rhythmic patterns commence again. 01:03:09.710 --> 01:03:16.250 But and we also see evidence that you know at one age for example we're recording from the red nucleus, 01:03:16.830 --> 01:03:22.210 and we see rhythmic activity or actually I should say very little rhythmic activity 01:03:22.210 --> 01:03:26.430 but just a four day difference from eight days of age to twelve days of age 01:03:26.430 --> 01:03:29.130 all of a sudden, all of this rhythmic activity is coming in. 01:03:29.510 --> 01:03:34.290 And if we anesthetize or inactivate the cerebellum, 01:03:35.082 --> 01:03:38.082 We get rid of all of that. So it appears as if the cerebellum, 01:03:38.082 --> 01:03:42.462 just that four-day period, is now providing rhythmic activity into the red nucleus. 01:03:43.082 --> 01:03:47.122 And so we're trying to follow that entire circuit to understand how that occurs. 01:03:47.302 --> 01:03:51.102 But it's a very dramatic effect. The difference between recording from the red 01:03:51.102 --> 01:03:55.222 nucleus of an eight-day-old and a 12-day-old is night and day in so many different dimensions. 01:03:55.282 --> 01:03:59.622 So that turns out to be a really interesting, potentially sensitive period for 01:03:59.622 --> 01:04:00.602 the development of the system. 01:04:00.602 --> 01:04:04.542 But now, if we talk about seeing or not seeing this kind of rhythmic activity. 01:04:05.902 --> 01:04:10.682 I mean, if you look at the awake brain, of course, it's configured in a very 01:04:10.682 --> 01:04:11.842 different kind of dynamical state. 01:04:11.922 --> 01:04:14.502 The way the thalamus will operate is very different. 01:04:15.502 --> 01:04:19.882 Right now, it will be much more in, let's say, a mode where it is passing more 01:04:19.882 --> 01:04:23.442 high-frequency responses. It's not hyperpolarized so much. 01:04:23.722 --> 01:04:27.602 So it might be the case that you still see these kind of low-frequency events, 01:04:27.602 --> 01:04:31.602 but they're masked, if you want, or much more attenuated because of the ongoing 01:04:31.602 --> 01:04:33.722 activity of the thalamocortical system. 01:04:34.142 --> 01:04:38.882 So is that the way you think about it? Yeah, I mean, I think we're still very 01:04:38.882 --> 01:04:40.982 early in the process of trying to understand this. 01:04:41.062 --> 01:04:46.382 I mean, the motor system, the actual overt behaviors of these infant rats, 01:04:47.042 --> 01:04:50.482 I mean, if you think about, you know, like a third trimester human infant, 01:04:50.562 --> 01:04:53.142 the behaviors are fairly limited in their complexity. 01:04:53.142 --> 01:04:58.362 And, and, um, and so, and the thalamocortical contributions are minimal. 01:04:58.502 --> 01:05:02.962 So we're not seeing a lot in terms of the complex rhythms that you see later 01:05:02.962 --> 01:05:05.082 in development when behaviors become more complex. 01:05:05.662 --> 01:05:10.902 And so in the way you described the system, even though we're talking about the learning, 01:05:11.122 --> 01:05:15.622 the development of, of, of a sensory motor system and motor control in the, 01:05:15.622 --> 01:05:19.702 in the motor control literature, people are very much carried away by this more, 01:05:19.802 --> 01:05:23.122 let's say, pseudo formalistic perspectives, like it's all Bayesian and it's 01:05:23.122 --> 01:05:25.082 inference and it's forward models and so on. 01:05:25.362 --> 01:05:29.702 And so many things have given us, let's say, a handle on certain aspects of motor control. 01:05:30.735 --> 01:05:33.695 But what's interesting is that in your analysis of the system, 01:05:33.755 --> 01:05:37.835 you don't really seem to build on those constructs. They don't seem to give 01:05:37.835 --> 01:05:41.195 you leverage in trying to understand the development of this motor system. 01:05:41.475 --> 01:05:46.475 So how do you see what you do and your data and also your interpretation relate 01:05:46.475 --> 01:05:49.275 then to the more standard field of motor control? 01:05:51.055 --> 01:05:56.835 Well, that's a great and deep question. So, yes, you know, I've read the literature. 01:05:56.835 --> 01:06:01.975 I, um, and one thing that always strikes me is there's always a little box that 01:06:01.975 --> 01:06:06.695 says, you know, prediction, but there's no box that says where that prediction comes from. 01:06:07.115 --> 01:06:09.935 And I think that is the missing developmental piece. I mean, 01:06:09.935 --> 01:06:11.515 developmentalists always, 01:06:11.635 --> 01:06:16.475 I mean, it's like, it's, it's, it's what we talk about over beer is, 01:06:16.555 --> 01:06:21.935 is how it gets, it doesn't get integrated into these formal models because unfortunately 01:06:21.935 --> 01:06:24.035 the formal modeling and then from a developmental perspective, 01:06:24.215 --> 01:06:26.135 there's a very low, well, you can tell me, right? 01:06:26.135 --> 01:06:28.535 How much do you know about a developing model? 01:06:28.655 --> 01:06:31.175 And I've talked to computational modelers about it. 01:06:31.495 --> 01:06:34.935 Most people I've talked to have not been interested in modeling it that way. 01:06:35.015 --> 01:06:37.115 But here's my challenge then to that community. 01:06:38.035 --> 01:06:41.795 Wouldn't it be better if we understood how a system develops computationally 01:06:41.795 --> 01:06:43.835 and in the process add it on? 01:06:44.015 --> 01:06:47.575 So know what is the simplest computational aspect of a system? 01:06:47.735 --> 01:06:49.615 So take the system we're working on. 01:06:49.795 --> 01:06:53.915 Wouldn't you want to know whether or not the inferior olive is doing an error 01:06:53.915 --> 01:06:55.655 signal early in development or not? 01:06:56.135 --> 01:06:58.975 And when it starts to have an error signal, then when you add that on, 01:06:59.095 --> 01:07:01.755 what kind of change does that have to the behavior of the animals? 01:07:01.835 --> 01:07:04.415 And by understanding the development of the system, wouldn't you learn something 01:07:04.415 --> 01:07:09.555 more about what are the essential computational ingredients to the behavior at each stage? 01:07:09.835 --> 01:07:12.515 And what things are critical, necessary, and what things are not? 01:07:13.315 --> 01:07:18.455 I think that is a missing perspective from the computational community. 01:07:18.455 --> 01:07:23.035 I think we would gain so much from being able to take development seriously 01:07:23.035 --> 01:07:27.615 and try to build these models in a way that mimics the developmental process. 01:07:29.790 --> 01:07:34.510 I think something we might touch on before we finish that listeners might be 01:07:34.510 --> 01:07:37.770 interested in is the effect of sleep deprivation. 01:07:38.390 --> 01:07:43.670 So if I take smart drugs and I don't go to sleep for a month, 01:07:43.770 --> 01:07:45.970 am I going to see some... You can take stupid drugs for the same thing. 01:07:46.610 --> 01:07:50.410 Am I going to see any motor consequences? What would your theory predict? 01:07:51.790 --> 01:07:58.810 Well, I don't know how much... I mean, anybody who's engaged in self-deprivation 01:07:58.810 --> 01:08:03.890 for whatever reason, probably has noticed that motor coordination is one of the things that goes. 01:08:04.230 --> 01:08:07.970 You know, you'll stumble around a little bit more, but you also have a lot of perceptual problems. 01:08:08.370 --> 01:08:12.850 So it seems as if from that standpoint, for whatever reason, 01:08:12.950 --> 01:08:16.090 because it's not really known, you know, what's happening in that situation. 01:08:16.250 --> 01:08:20.290 But several days of sleep deprivation and you're going to look a bit drunk, 01:08:20.450 --> 01:08:25.490 which is interesting since drunkenness is very much mediated by the the cerebellum, 01:08:25.490 --> 01:08:27.550 but, um, at least the behavioral component. 01:08:28.070 --> 01:08:32.930 Um, but you know, the, the, the experiments that have been done on deprivation 01:08:32.930 --> 01:08:35.150 have largely focused on the physiological consequences. 01:08:35.870 --> 01:08:40.390 Um, I, I'm sure there's, and some aspects of a sequence learning and things 01:08:40.390 --> 01:08:43.670 like that have also been studied, but, um, uh, 01:08:43.830 --> 01:08:48.530 yeah, I mean, there, there was a drug that came out about 10 years ago now called modafinil, 01:08:48.530 --> 01:08:51.510 so known as provigil that people thought was going to be, 01:08:51.510 --> 01:08:54.950 you know the great the great keep you awake drug um but 01:08:54.950 --> 01:08:57.710 i don't think it's it's advisable to keep yourself 01:08:57.710 --> 01:09:00.530 awake on drugs like that you you know do 01:09:00.530 --> 01:09:03.370 so at your own risk so so mark 01:09:03.370 --> 01:09:06.270 and i mean you are really 01:09:06.270 --> 01:09:11.950 digging very deep in in in a phenomenon that that from the outset might look 01:09:11.950 --> 01:09:14.990 like almost trivial if you look at the brain as a whole right because we think 01:09:14.990 --> 01:09:18.530 about memory and consciousness or whatever but now you found that actually by 01:09:18.530 --> 01:09:23.170 really understanding the twitch Which you actually can really gain a deep insight 01:09:23.170 --> 01:09:25.210 how brains operate and configure themselves. 01:09:25.430 --> 01:09:31.270 So if we would like to follow, now in your tradition, what is Mark's law that 01:09:31.270 --> 01:09:34.230 we should write on the wall and follow every day? Yeah. 01:09:35.470 --> 01:09:39.050 Um, just one, I only get one law. Yeah, we're going to have to, no problem. 01:09:39.210 --> 01:09:44.650 Well, I think, you know, the, the, the, I'll say it from a, from a scientist's 01:09:44.650 --> 01:09:49.210 perspective, you know, it, it can be a bit scary studying something that everybody, 01:09:49.450 --> 01:09:52.950 everybody, uh, considered to be of no consequence. 01:09:53.470 --> 01:09:59.530 And one of the joys I get out of doing science is to try to do things that people 01:09:59.530 --> 01:10:01.290 find counterintuitive and surprising. 01:10:01.910 --> 01:10:05.650 There are risks with that. I mean, it could be that everything we've ever done, 01:10:05.670 --> 01:10:09.830 you know, turns out to be of no consequence whatsoever, in which case the egg 01:10:09.830 --> 01:10:11.490 on my face will never come off. 01:10:12.110 --> 01:10:16.190 But, you know, after you follow the data and you try to generate good hypotheses 01:10:16.190 --> 01:10:21.550 and you try to keep an open mind as best as you can, and you let things go as 01:10:21.550 --> 01:10:26.930 they have. And, and in this particular instance, I've, I'm, I'm personally relieved at this point. 01:10:26.970 --> 01:10:30.830 I think it's going to turn out to be, uh, of, of great value. 01:10:31.190 --> 01:10:35.450 Um, but there's always that possibility you're wrong and that's just the nature of science. 01:10:35.550 --> 01:10:40.470 So I guess my law would be, um, we need to encourage risk-taking, 01:10:40.570 --> 01:10:45.070 you know, I mean, it's very easy to, to, to, for, for all of us to study the same exact thing. 01:10:45.070 --> 01:10:48.990 But it's, I think it's also nice to, to enjoy being the first person to study 01:10:48.990 --> 01:10:51.910 something that no, you know, not only that people weren't interested in, 01:10:51.950 --> 01:10:54.410 but actually people thought were of no consequence whatsoever. 01:10:54.470 --> 01:10:59.070 And I get, I actually, I do get a lot of joy in, in, in sort of digging things 01:10:59.070 --> 01:11:03.150 up and seeing where they lead and being surprised. Right. So take risk. 01:11:03.750 --> 01:11:06.710 But then, so five years now, Tony likes traveling. Yeah. 01:11:07.186 --> 01:11:11.926 Tony will come visit you, and he will come and check whether you actually found 01:11:11.926 --> 01:11:14.826 evidence for a hypothesis you're going to generate for us today. 01:11:15.866 --> 01:11:20.406 So what's the most ambitious hypothesis you want to see realized and confirmed 01:11:20.406 --> 01:11:23.146 five years from now in your program? 01:11:23.666 --> 01:11:27.426 Well, there are several. So one would be that we want to show that Twitches 01:11:27.426 --> 01:11:30.766 are playing an active role in plasticity and the organization of the system. 01:11:30.766 --> 01:11:35.846 We want to understand what parts of the system are providing the critical inputs 01:11:35.846 --> 01:11:39.126 that lead to these different aspects of modulation. 01:11:39.586 --> 01:11:44.566 I want personally to understand how twitching changes is differentially expressed 01:11:44.566 --> 01:11:48.146 in different species and across the lifespan in different animals. 01:11:48.146 --> 01:11:52.106 And I want to know, I have, I want to understand how body morphology, 01:11:52.246 --> 01:11:54.886 like whether or not you have a trunk or whether or not you have a fin or whether, 01:11:54.946 --> 01:11:58.906 you know, whatever, uh, how your body, whether or not the most important parts 01:11:58.906 --> 01:12:02.166 of your, of your, of your bodies are the ones that twitch. 01:12:02.166 --> 01:12:08.606 And then I want to understand, especially in humans, whether or not we can see 01:12:08.606 --> 01:12:12.666 that twitching actually can play a role in the maintenance and recovery of function 01:12:12.666 --> 01:12:16.186 that happens after skill learning, stroke, 01:12:16.466 --> 01:12:20.326 peripheral damage, whatever, so that it actually might be playing a role in 01:12:20.326 --> 01:12:21.866 those sorts of processes as well. 01:12:21.966 --> 01:12:26.686 So really just sort of proving the foundation and expanding it into other domains, 01:12:26.846 --> 01:12:28.846 I think that's where we need to go. All right, great. 01:12:28.986 --> 01:12:32.046 Mark Bloomberg, thank you very much for this conversation. Thank you. Thank you. 01:12:35.386 --> 01:12:41.086 But I don't share your utopic dream of a world running around with submissive 01:12:41.086 --> 01:12:43.346 roboticists. Sorry, Mark. 01:12:44.626 --> 01:12:49.506 That was going too far. A little weak on the dreaming, I guess. 01:12:52.086 --> 01:12:58.386 I guess that's a price you paid, you know. I dream of a world of roboticists. 01:12:58.386 --> 01:13:00.506 So beautiful. My ideal organization. 01:13:01.986 --> 01:13:07.286 I have been known to engage in hyperbole, so, you know. Well, you succeeded. 01:13:08.766 --> 01:13:17.686 That was great. Very good. Thank you. 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